Barbituric acid derivatives as inhibitors of TNF-α converting enzyme (TACE) and/or matrix metalloproteinases

ABSTRACT

The present application describes novel barbituric acid derivatives of formula I: 
                 
 
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, L, R 1 , W, Z, U a , X a , Y a , and Z a  are defined in the present specification, which are useful as TNF-α converting enzyme (TACE) and matrix metalloproteinases (MMP) inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. ProvisionalApplication No. 60/342,649, filed Dec. 20, 2001, the disclosure of whichis incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates generally to novel barbituric acid derivatives asinhibitors of TNF-α converting enzyme (TACE), matrix metalloproteinases(MMP), aggrecanse or a combination thereof, pharmaceutical compositionscontaining the same, and methods of using the same.

BACKGROUND OF THE INVENTION

There is now a body of evidence that metalloproteases (MP) are importantin the uncontrolled breakdown of connective tissue, includingproteoglycan and collagen, leading to resorption of the extracellularmatrix. This is a feature of many pathological conditions, such asrheumatoid and osteoarthritis; corneal, epidermal, or gastriculceration; tumor metastasis or invasion; periodontal disease; and bonedisease. Normally these catabolic enzymes are tightly regulated at thelevel of their synthesis as well as at their level of extracellularactivity through the action of specific inhibitors, such asalpha-2-macroglobulins and TIMPs (tissue inhibitors of metalloprotease),which form inactive complexes with the MP's.

Osteo- and rheumatoid arthritis (OA and RA respectively) are destructivediseases of articular cartilage characterized by localized erosion ofthe cartilage surface. Findings have shown that articular cartilage fromthe femoral heads of patients with OA, for example, had a reducedincorporation of radiolabeled sulfate over controls, suggesting thatthere must be an enhanced rate of cartilage degradation in OA (Mankin etal. J. Bone Joint Surg. 1970, 52A, 424-434). There are four classes ofprotein degradative enzymes in mammalian cells: serine, cysteine,aspartic, and metalloprotease. The available evidence supports that itis the metalloproteases that are responsible for the degradation of theextracellular matrix of articular cartilage in OA and RA. Increasedactivities of collagenases and stromelysin have been found in OAcartilage and the activity correlates with the severity of the lesion(Mankin et al. Arthritis Rheum. 1978, 21, 761-766, Woessner et al.Arthritis Rheum. 1983, 26, 63-68, and Woessner et al. Arthritis Rheum.1984, 27, 305-312). In addition, aggrecanase has been identified asproviding the specific cleavage product of proteoglycan found in RA andOA patients (Lohmander L. S. et al. Arthritis Rheum. 1993, 36, 1214-22).

Therefore, metalloproteases (MP) have been implicated as the key enzymesin the destruction of mammalian cartilage and bone. It can be expectedthat the pathogenesis of such diseases can be modified in a beneficialmanner by the administration of MP inhibitors, and many compounds havebeen suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem.1990, 25, 175-184, AP, San Diego).

Tumor necrosis factor-α (TNF-α) is a cell-associated cytokine that isprocessed from a 26 kd precursor form to a 17 kd soluble form. TNF-α hasbeen shown to be a primary mediator in humans and in animals ofinflammation, fever, and acute phase responses, similar to thoseobserved during acute infection and shock. Excess TNF-α has been shownto be lethal. There is now considerable evidence that blocking theeffects of TNF-α with specific antibodies can be beneficial in a varietyof circumstances including autoimmune diseases such as RA (Feldman etal, Lancet 1994, 344, 1105), non-insulin dependent diabetes melitus(Lohmander, L. S. et al. Arthritis Rheum. 1993, 36, 1214-22), andCrohn's disease (MacDonald et al. Clin. Exp. Immunol. 1990, 81, 301).

Compounds which inhibit the production of TNF-α are therefore oftherapeutic importance for the treatment of inflammatory disorders. Thisinvention describes molecules that inhibit TNF-α converting enzyme(TACE) and hence the secretion of active TNF-α from cells. These novelmolecules provide a means of mechanism based therapeutic interventionfor diseases including but not restricted to septic shock, haemodynamicshock, sepsis syndrome, post ischemic reperfusion injury, malaria,Crohn's disease, inflammatory bowel diseases, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic diseases,cachexia, graft rejection, cancer, diseases involving angiogenesis,autoimmune diseases, skin inflammatory diseases, OA, RA, multiplesclerosis, radiation damage, hyperoxic alveolar injury, periodontaldisease, HIV, and non-insulin dependent diabetes melitus.

Since excessive TNF-α production has been noted in several diseaseconditions also characterized by MMP-mediated tissue degradation,compounds which inhibit both MMPs and TNF-α production may also have aparticular advantage in diseases where both mechanisms are involved.

It is desirable to find new compounds with improved pharmacologicalcharacteristics compared with known MMP and/or TACE inhibitors. Forexample, it is preferred to find new compounds with improved MMP and/orTACE inhibitory activity and selectivity for an MMP and/or TACE versusother metalloproteases (e.g., specificity for one MMP versus another).It is also desirable and preferable to find compounds with advantageousand improved characteristics in one or more of the following categories:(a) pharmaceutical properties (e.g., solubility, permeability, andamenability to sustained release formulations); (b) dosage requirements(e.g., lower dosages and/or once-daily dosing); (c) factors whichdecrease blood concentration peak-to-trough characteristics (e.g.,clearance and/or volume of distribution); (d) factors that increase theconcentration of active drug at the receptor (e.g., protein binding andvolume of distribution); (e) factors that decrease the liability forclinical drug-drug interactions (e.g., cytochrome P450 enzyme inhibitionor induction); (f) factors that decrease the potential for adverseside-effects (e.g., pharmacological selectivity beyond serine proteases,potential chemical or metabolic reactivity, and limited CNSpenetration); and (g) factors that improve manufacturing costs orfeasibility (e.g., difficulty of synthesis, number of chiral centers,chemical stability, and ease of handling).

The compounds of the present invention act as inhibitors of MPs, inparticular TACE, MMPs, and/or aggrecanase. These novel molecules areprovided as anti-inflammatory compounds and cartilage protectingtherapeutics.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel barbituric acidderivatives useful as MMP, TACE, and/or aggrecanase inhibitors orpharmaceutically acceptable salts or prodrugs thereof.

The present invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating inflammatorydisorders, comprising: administering to a mammal, in need of suchtreatment, a therapeutically effective amount of at least one of thecompounds of the present invention or a pharmaceutically acceptable saltor prodrug form thereof.

The present invention provides a method of treating a condition ordisease mediated by MMPs, TACE, aggrecanase, or a combination thereof ina mammal, comprising: administering to the mammal in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

The present invention provides a method comprising: administering acompound of the present invention or a pharmaceutically acceptable saltor prodrug form thereof in an amount effective to treat a condition ordisease mediated by MMPs, TACE, aggrecanase, or a combination thereof.

The present invention provides novel compounds of the present inventionfor use in therapy.

The present invention provides the use of novel compounds of the presentinvention for the manufacture of a medicament for the treatment of acondition or disease mediated by MMPs, TACE, aggrecanase, or acombination thereof.

The present invention provides a method for treating inflammatorydisorders, comprising: administering, to a mammal in need of suchtreatment, a therapeutically effective amount of one of the compounds ofthe present invention, in combination with one or more additionalanti-inflammatory agents selected from selective COX-2 inhibitors,interleukin-1 antagonists, dihydroorotate synthase inhibitors, p38 MAPkinase inhibitors, TNF-α inhibitors, TNF-α sequestration agents, andmethotrexate.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat compounds of formula I:

or pharmaceutically acceptable salt or prodrug forms thereof, wherein A,B, L, R¹, W, Z, U^(a), X^(a), Y^(a), and Z^(a) are defined below, areeffective as MMP and/or TACE inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in an embodiment, the present invention provides a novelcompound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof,wherein;

-   A is C(═O), C(═S) or CH₂;-   B is O or S;-   L is O or S;-   W is selected from (CR^(a)R^(a1))_(m), C₂₋₃ alkenylene, and C₂₋₃    alkynylene;-   Z is selected from:    -   a C₆₋₁₀ aryl substituted with 0-5 R^(b) and a 5-14 membered        heteroaryl comprising carbon atoms and 1-4 heteroatoms selected        from the group consisting of N, O, and S(O)_(p), and substituted        with 0-5 R^(b);-   U^(a) is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1),    NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1),    NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1);-   X^(a) is absent or is selected from C₁₋₁₀ alkylene, C₂₋₁₀    alkenylene, and C₂₋₁₀ alkynylene;-   Y^(a) is absent or is selected from O, NR^(a1), S(O)_(p), and C(O);-   provided that U^(a)—X^(a)—Y^(a) forms a linker group of two or more    backbone atoms;-   Z^(a) is selected from a C₃₋₁₃ carbocycle substituted with 0-5 R^(c)    and a 5-14 membered heterocycle comprising carbon atoms and 1-4    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0-5 R^(c);-   provided that Z^(a) is other than dihydro-2-oxo-thien-3-yl;-   provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form a    N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p), or S(O)_(p)—S(O)_(p)    group;-   R¹ is selected from CHF₂, CH₂F, CF₃, C₁₋₆ alkylene-Q, C₂₋₆    alkenylene-Q, C₂₋₆ alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)OC(O)    (CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)OC(O)OR^(a1),    (CR^(a)R^(a1))_(r1)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)SO₂NR^(a)R^(a1), a C₃₋₁₃ carbocycle    substituted with 0-5 R^(d), and a 5-14 membered heterocycle    comprising carbon atoms and 1-4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0-5 R^(d);-   Q, at each occurrence, is independently selected from H, CHF₂, CH₂F,    CF₃, a C₃₋₁₃ carbocycle substituted with 0-5 R^(d), and a 5-14    membered heterocycle comprising carbon atoms and 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p), and    substituted with 0-5 R^(d);-   R^(a), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, and benzyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-1 R^(e), C₂₋₆ alkenyl substituted with 0-1    R^(e), C₂₋₆ alkynyl substituted with 0-1 R^(e), and —(CH₂)_(r)-3-8    membered carbocyclic or heterocyclic ring comprising carbon atoms    and 0-2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p),    and substituted with 0-3 R^(e);-   alternatively, R^(a) and R^(a1), when attached to a nitrogen, are    taken together with the nitrogen to which they are attached, form a    5 or 6 membered heterocycle comprising carbon atoms and 0-1    additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);-   R^(a2), at each occurrence, is independently selected from C₁₋₄    alkyl, phenyl, and benzyl;-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl substituted with 0-1 R^(c1), C₂₋₆ alkenyl substituted with 0-1    R^(c1), C₂₋₆ alkynyl substituted with 0-1 R^(c1), and —(CH₂)_(r)-3-8    membered carbocyclic or heterocyclic ring comprising carbon atoms    and 0-2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p),    and substituted with 0-3 R^(c1);-   R^(b), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-1 R^(c1), OR^(a), SR^(a), Cl, F, Br, I, ═O, —CN,    NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1),    C(S)NR^(a)R^(a1), NR^(a)C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1),    NR^(a)C(O)OR^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),    NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3),    S(O)_(p)R^(a3), CF₃, CF₂CF₃, CHF₂, CH₂F, and phenyl;-   R^(c), at each occurrence, is independently selected from H, OR^(a),    Cl, F, Br, I, ═O, —CN, NO₂, CF₃, CF₂CF₃, CH₂F, CHF₂,    (CR^(a)R^(a1))_(r)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NCN)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NR^(a))NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)C(═NOR^(a))NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a)OH, (CR^(a)R^(a1))_(r1)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(S)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(S)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)OC(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3),    (CR^(a)R^(a1))_(r)NR^(a)SO₂NR^(a)R^(a1);    -   C₁₋₆ alkyl substituted with 0-2 R^(c1);    -   C₂₋₆ alkenyl substituted with 0-2 R^(c1);    -   C₂₋₆ alkynyl substituted with 0-2 R^(c1);    -   (CR^(a)R^(a1))_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(c1);        and    -   (CR^(a)R^(a1))_(r)-5-14 membered heterocycle comprising carbon        atoms and 1-4 heteroatoms selected from the group consisting of        N, O, and S(O)_(p), and substituted with 0-2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3-11 membered carbocycle or    heterocycle substituted with 0-2 R^(c1) and comprising: carbon    atoms, 0-4 ring heteroatoms selected from O, N, and S(O)_(p), and    0-2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond;-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5-7 membered carbocyclic or heterocyclic ring D    substituted with 0-2 R^(c1) and consisting of carbon atoms, 0-2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0-3 double bonds;-   R^(c1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a),    C(O)OR^(a), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1),    OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, and    CHF₂;-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-2 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl,    F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a),    C(O)NR^(a)R^(a1), C(S)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1),    OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a3), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, CF₂CF₃, (CH₂)_(r)—C₃₋₁₀    carbocycle substituted with 0-2 R^(e), and a (CH₂)_(r)-5-14 membered    heterocycle comprising carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0-2 R^(e);-   R^(e), at each occurrence, is independently selected from H, C₁₋₆    alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a), C(O)R^(a),    C(O)OR^(a), C(O)NR^(a)R^(a), R^(a)NC(O)NR^(a)R^(a),    OC(O)NR^(a)R^(a), R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a),    NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a), OS(O)₂NR^(a)R^(a),    NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, and    CHF₂;-   m, at each occurrence, is selected from 0, 1, 2 and 3;-   p, at each occurrence, is selected from 0, 1, and 2;-   r, at each occurrence, is selected from 0, 1, 2, 3, and 4;-   r1, at each occurrence, is selected from 0, 1, 2, 3, and 4;-   provided that when A is C(═O), B is O, L is O,    -   (i) R¹ is C₁₋₄ alkyl, allyl, isopropyl, or 2-propynyl,        U^(a)—X^(a)—Y^(a) is —OCH₂—, and Z is phenylene, then Z^(a) is        other than phenyl;    -   (ii) R¹ is C₁₋₄ alkyl, allyl, isopropyl, or 2-propynyl, Z is        phenylene, and Z^(a) is phenyl, then U^(a)—X^(a)—Y^(a) forms        other than —OCH₂—;    -   (iii) R¹ is C₁₋₄ alkyl, U^(a)—X^(a)—Y^(a) is —OCH₂— or —CH₂OCO—,        and Z is phenylene, then Z^(a) is other than phenyl;    -   (iv) R¹ is C₁₋₄ alkyl, Z is phenylene, and Z^(a) is phenyl, then        U^(a)—X^(a)—Y^(a) forms other than —OCH₂— or —CH₂OCO—;    -   (v) R¹ is OH, U^(a)—X^(a)—Y^(a) is CONH, and Z is naphthalenyl,        then Z^(a) is other than phenyl;    -   (vi) R¹ is OH, Z is naphthalenyl, and Z^(a) is phenyl, then        U^(a)—X^(a)—Y^(a) forms other than CONH; and-   provided that when A is C(═O), B is O, L is O, R¹ is OH or OMe,    -   (i) U^(a)—X^(a)—Y^(a) is —NHCH₂—, —N(Me)CH₂—, —N(Et)CH₂— or        —N(COMe)CH₂—, and Z is phenylene, then Z^(a) is other than        phenyl,    -   (ii) Z is phenylene and Z^(a) is phenyl, then U^(a)—X^(a)—Y^(a)        forms other than —NHCH₂—, —N(Me)CH₂—, —N(Et)CH₂— or        —N(COMe)CH₂—.

[2] In another embodiment, the present invention provides a novelcompound, wherein;

-   W is (CHR^(a))_(m) or C₂₋₃ alkenylene;-   U^(a) is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH),    C(O)O, C(O)NR^(a1), NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1), and    NR^(a1)S(O)_(p);-   X^(a) is absent or is selected from C₁₋₄ alkylene, C₂₋₄ alkenylene,    and C₂₋₄ alkynylene;-   Y^(a) is absent or is selected from O and NR^(a1);-   provided that U^(a)—X^(a)—Y^(a) forms a linker group of two or more    backbone atoms;-   R¹ is selected from CHF₂, CH₂F, CF₃, C₁₋₆ alkylene-Q, C₂₋₆    alkenylene-Q, C₂₋₆ alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)C(O)NR^(a) (CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)NR^(a)C(O) (CR^(a)R^(a1))_(r1)-Q,    (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q, a C₃₋₁₀ carbocycle    substituted with 0-5 R^(d), and a 5-10 membered heterocycle    comprising carbon atoms and 1-4 heteroatoms selected from the group    consisting of N, O, and S(O)_(p), and substituted with 0-5 R^(d);-   Q, at each occurrence, is independently selected from H, CF₃, a    C₃₋₁₃ carbocycle substituted with 0-5 R^(d), and a 5-14 membered    heterocycle comprising carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0-5 R^(d);-   R^(c), at each occurrence, is independently selected from H, OR^(a),    Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1), CF₃,    (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1),    (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3);    -   C₁₋₆ alkyl substituted with 0-1 R^(c1);    -   C₂₋₆ alkenyl substituted with 0-1 R^(c1);    -   C₂₋₆ alkynyl substituted with 0-1 R^(c1);    -   (CH₂)_(r)—C₃₋₆ carbocycle substituted with 0-2 R^(c1); and    -   (CH₂)_(r)-5-6 membered heterocycle comprising carbon atoms and        1-4 heteroatoms selected from the group consisting of N, O, and        S(O)_(p), and substituted with 0-2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3-8 membered carbocycle or    heterocycle substituted with 0-2 R^(c1) and comprising: carbon    atoms, 0-4 ring heteroatoms selected from O, N, and S(O)_(p), and    0-2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond; and-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5-7 membered carbocyclic or heterocyclic ring D    substituted with 0-2 R^(c1) and consisting of carbon atoms, 0-2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0-3 double bonds.

[3] In another embodiment, the present invention provides a novelcompound, wherein;

-   A is C(═O) or CH₂;-   B is O;-   L is O;-   Z is selected from:    -   phenyl substituted with 0-5 R^(b);    -   naphthyl substituted with 0-5 R^(b); and    -   a 5-14 membered heteroaryl comprising carbon atoms and 1-4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p), and substituted with 0-5 R^(b);-   U^(a) is absent or is selected from: O, NR^(a1), C(O), C(O)NR^(a1),    NR^(a1)C(O), and S(O)_(p);-   provided that U^(a)—X^(a)—Y^(a) forms a linker group of two or more    backbone atoms;-   Z^(a) is selected from a C₅₋₁₀ carbocycle substituted with 0-5 R^(c)    and a 5-14 membered heterocycle comprising carbon atoms and 1-4    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and substituted with 0-5 R^(c);-   provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form a    N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p)    group;-   Q, at each occurrence, is independently selected from H, a C₃₋₁₀    carbocycle substituted with 0-3 R^(d), and a 5-14 membered    heterocycle comprising carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0-3 R^(d);-   R^(a), at each occurrence, is independently selected from H and C₁₋₆    alkyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, and benzyl;-   alternatively, R^(a) and R^(a1), when attached to a nitrogen, are    taken together with the nitrogen to which they are attached, form a    5 or 6 membered heterocycle comprising carbon atoms and 0-1    additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p);-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, and —(CH₂)_(r)-3-8 membered carbocyclic or    heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms    selected from N, NR^(a2), O, and S(O)_(p), and substituted with 0-3    R^(c1);-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3);    -   C₃₋₆ carbocycle substituted with 0-2 R^(c1); and    -   5-6 membered heterocycle comprising carbon atoms and 1-4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p), and substituted with 0-2 R^(c1);-   alternatively, when two R^(c) groups are attached to the same carbon    atom, they form a spiro ring C that is a 3-8 membered carbocycle or    heterocycle substituted with 0-2 R^(c1) and comprising: carbon    atoms, 0-4 ring heteroatoms selected from O, N, and S(O)_(p), and    0-2 double bonds, provided that ring C contains other than a S—S,    O—O, or S—O bond;-   alternatively, when two R^(c) groups are attached to adjacent carbon    atoms, together with the carbon atoms to which they are attached    they form a 5-6 membered carbocyclic or heterocyclic ring D    substituted with 0-2 R^(c1) and consisting of carbon atoms, 0-2    heteroatoms selected from the group consisting of N, O, and    S(O)_(p), and 0-3 double bonds;-   R^(c1), at each occurrence, is independently selected from H, C₁₋₄    alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)OR^(a), and    C(O)NR^(a)R^(a1);-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-2 R^(e), OR^(a), Cl, F, Br, ═O, —CN, NO₂,    NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a), C(O)NR^(a)R^(a1),    S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃,    (CH₂)_(r)—C₃₋₆ carbocycle substituted with 0-2 R^(e), and a 5-6    membered heterocycle comprising carbon atoms and 1-4 heteroatoms    selected from the group consisting of N, O, and S(O)_(p); and-   R^(e), at each occurrence, is independently selected from H, C₁₋₄    alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)OR^(a), and    C(O)NR^(a)R^(a).

[4] In another embodiment, the present invention provides a novelcompound, wherein;

-   W is (CH₂)_(m) or C₂₋₃ alkenylene;-   Z selected from:    -   phenyl substituted with 0-3 R^(b);    -   naphthyl substituted with 0-3 R^(b);    -   a 5-10 membered heteroaryl substituted with 0-3 R^(b) and        selected from the group: furanyl, thiazolyl, oxazolyl,        imidazolyl, isothiazolyl, isoxazolyl, thiophenyl, triazinyl,        pyridyl, pyrimidinyl, pyridoimidazole, indolyl, benzimidazolyl,        benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl,        benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl,        quinolinyl, isoquinolinyl, indazolyl, isobenzofuranyl,        isoindazolyl, isoindolyl, isoquinolinyl, and quinazolinyl;-   Z^(a) is selected from phenyl substituted with 0-3 R^(c); naphthyl    substituted with 0-3 R^(c); and a 5-10 membered heterocycle    substituted with 0-3 R^(c) and selected from the group: furanyl,    tetrahydrofuranyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl,    isoxazolyl, 4,5-dihydro-isoxazolyl, thiophenyl, triazinyl, pyridyl,    pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl,    pyrazolyl, pyridoimidazole, pyrrolidinyl, pyrrolinyl, indolyl,    indolinyl, benzimidazolyl, benzothiazinyl, benzofuranyl,    benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,    benzisoxazolyl, benzisothiazolyl, quinolinyl, tetrahydroquinolinyl,    isoquinolinyl, tetrahydroisoquinolinyl, indazolyl, isobenzofuranyl,    isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,    methylenedioxyphenyl, quinazolinyl, thiadiazinyl, and    1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl;-   provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form a    N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p)    group;-   Q, at each occurrence, is independently selected from H, a C₃₋₆    carbocycle substituted with 0-3 R^(d), and a 5-10 membered    heterocycle comprising carbon atoms and 1-4 heteroatoms selected    from the group consisting of N, O, and S(O)_(p), and substituted    with 0-3 R^(d);-   R^(a), at each occurrence, is independently selected from H and C₁₋₆    alkyl;-   R^(a1), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, and benzyl;-   R^(a3), at each occurrence, is independently selected from H, C₁₋₆    alkyl, phenyl, and benzyl;-   R^(b), at each occurrence, is independently selected from C₁₋₄    alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a),    C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a3), and CF₃;-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3);    -   C₃₋₆ carbocycle substituted with 0-2 R^(c1); and    -   5-6 membered heterocycle comprising carbon atoms and 1-4        heteroatoms selected from the group consisting of N, O, and        S(O)_(p), and substituted with 0-2 R^(c1); and-   R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl    substituted with 0-1 R^(e), OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1),    C(O)R^(a1), C(O)OR^(a), C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1),    NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, and (CH₂)_(r)-phenyl    substituted with 0-2 R^(e).

[5] In another embodiment, the present invention provides a novelcompound, wherein;

-   Z is selected from:    -   phenyl substituted with 0-3 R^(b);    -   naphthyl substituted with 0-3 R^(b);    -   thiophenyl substituted with 0-2 R^(b);    -   oxazolyl substituted with 0-1 R^(b);    -   isoxazolyl substituted with 0-1 R^(b); and    -   thiazolyl substituted with 0-1 R^(b);-   U^(a) is absent or is O;-   X^(a) is selected from CH₂ and CH₂CH₂;-   Y^(a) is absent or is O;-   provided that U^(a)—X^(a)—Y^(a) forms a linker group of two or more    backbone atoms;-   Z^(a) is selected from phenyl substituted with 0-3 R^(c);    -   pyridyl substituted with 0-3 R^(c);    -   indolyl substituted with 0-3 R^(c);    -   quinolinyl substituted with 0-3 R^(c);    -   benzimidazolyl substituted with 0-3 R^(c); and    -   1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl substituted        with 0-3 R^(c);-   provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form a    N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p)    group;-   R¹ is selected from C₁₋₆ alkylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1),    (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q,    (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1),    -   a C₃₋₆ carbocycle substituted with 0-3 R^(d), and a 5-10        membered heterocycle comprising carbon atoms and 1-4 heteroatoms        selected from the group consisting of N, O, and S(O)_(p), and        substituted with 0-3 R^(d); and-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1),    and phenyl.

[6] In another embodiment, the present invention provides a novelcompound, wherein;

-   R¹ is selected from C₁₋₆ alkylene-Q, NR^(a)(CR^(a)R^(a1))_(r)-Q,    C(O)(CR^(a)R^(a1))_(r)-Q, C(O)OR^(a1), C(O)NR^(a)R^(a1),    NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q, NR^(a)C(O)OR^(a1),    S(O)_(p)(CR^(a)R^(a1))_(r)-Q, SO₂NR^(a)R^(a1), cyclopropyl    substituted with 0-1 R^(d), cyclopentyl substituted with 0-1 R^(d),    cyclohexyl substituted with 0-1 R^(d), phenyl substituted with 0-2    R^(d), and a heterocycle substituted with 0-3 R^(d), wherein the    heterocycle is selected from pyridyl, quinolinyl, thiazolyl,    furanyl, morpholinyl, imidazolyl, isoxazolyl, piperidinyl, and    piperazinyl;-   Q, at each occurrence, is independently selected from H, cyclopropyl    substituted with 0-1 R^(d), cyclopentyl substituted with 0-1 R^(d),    cyclohexyl substituted with 0-1 R^(d), phenyl substituted with 0-2    R^(d), and a heteroaryl substituted with 0-3 R^(d), wherein the    heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl,    imidazolyl, and isoxazolyl;-   R^(c), at each occurrence, is independently selected from H, C₁₋₆    alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O,    NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1),    (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1),    (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), and phenyl; and-   r, at each occurrence, is selected from 0, 1, 2, and 3.

[7] In another preferred embodiment, the present invention provides anovel compound selected from the group:

-   5-methyl-5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4,6(1H, 3H,    5H)-pyrimidinetrione;-   5-methyl-5-(2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}ethyl)-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   tert-butyl    5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4,6-trioxohexahydro-5-pyrimidinylcarbamate;-   5-amino-5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4,6(1H, 3H,    5H)-pyrimidinetrione;-   5-methyl-5-((2E)-3-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-propenyl)-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-methyl-5-(3-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}propyl)-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-methyl-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H, 3H,    5H)-pyrimidinetrione;-   5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-(1-piperidinyl)-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-(4-morpholinyl)-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   tert-butyl    4-(5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6-trioxohexahydro-5-pyrimidinyl)-1-piperazinecarboxylate;-   5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-(1-piperazinyl)-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-(4-methyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(2-phenylethyl)-1-piperazinyl]-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-(4-neopentyl-1-piperazinyl)-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-(4-isopropyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-(4-hexyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-(4-benzyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(3-phenylpropyl)-1-piperazinyl]-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(4-nitrophenyl)-1-piperazinyl]-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-[4-(2-hydroxyethyl)-1-piperazinyl]-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   4-[4-(5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6-trioxohexahydro-5-pyrimidinyl)-1-piperazinyl]butanoic    acid;-   N-methyl-4-[4-(5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6-trioxohexahydro-5-pyrimidinyl)-1-piperazinyl]butanamide;-   5-(4-acetyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-[4-(2,2-dimethylpropanoyl)-1-piperazinyl]-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(methylsulfonyl)-1-piperazinyl]-2,4,6(1H,    3H, 5H)-pyrimidinetrione;-   5-[4-(benzyloxy)phenyl]-5-methyldihydro-2,4(1H, 3H)-pyrimidinedione;-   5-methyl-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}dihydro-2,4(1H,    3H)-pyrimidinedione;-   tert-butyl    (5S)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4-dioxohexahydro-5-pyrimidinylcarbamate;-   (5S)-5-amino-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}dihydro-2,4(1H,    3H)-pyrimidinedione;-   5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-(4-piperidinyl)dihydro-2,4(1H,    3H)-pyrimidinedione;-   tert-butyl    5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4-dioxohexahydro-5-pyrimidinylcarbamate;-   5-amino-5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}dihydro-2,4(1H,    3H)-pyrimidinedione;-   (5S)-5-(dimethylamino)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}dihydro-2,4(1H,    3H)-pyrimidinedione;-   or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novelpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method fortreating an inflammatory disorder, comprising: administering to apatient in need thereof a therapeutically effective amount of a compoundof the present invention or a pharmaceutically acceptable salt formthereof.

In another embodiment, the present invention provides a novel method oftreating a condition or disease mediated by MMPs, TACE, aggrecanase, ora combination thereof in a mammal, comprising: administering to themammal in need of such treatment a therapeutically effective amount of acompound of the present invention or a pharmaceutically acceptable saltform thereof.

In another embodiment, the present invention provides a novel methodcomprising: administering a compound of the present invention or apharmaceutically acceptable salt form thereof in an amount effective totreat a condition or disease mediated by MMPs, TACE, aggrecanase, or acombination thereof.

In another embodiment, the present invention provides a novel method oftreating a disease or condition, wherein the disease or condition isselected from acute infection, acute phase response, age related maculardegeneration, alcoholic liver disease, allergy, allergic asthma,anorexia, aneurism, aortic aneurism, asthma, atherosclerosis, atopicdermatitis, autoimmune disease, autoimmune hepatitis, Bechet's disease,cachexia, calcium pyrophosphate dihydrate deposition disease,cardiovascular effects, chronic fatigue syndrome, chronic obstructionpulmonary disease, coagulation, congestive heart failure, cornealulceration, Crohn's disease, enteropathic arthropathy, Felty's syndrome,fever, fibromyalgia syndrome, fibrotic disease, gingivitis,glucocorticoid withdrawal syndrome, gout, graft versus host disease,hemorrhage, HIV infection, hyperoxic alveolar injury, infectiousarthritis, inflammation, intermittent hydrarthrosis, Lyme disease,meningitis, multiple sclerosis, myasthenia gravis, mycobacterialinfection, neovascular glaucoma, osteoarthritis, pelvic inflammatorydisease, periodontitis, polymyositis/dermatomyositis, post-ischaemicreperfusion injury, post-radiation asthenia, psoriasis, psoriaticarthritis, pulmonary emphysema, pydoderma gangrenosum, relapsingpolychondritis, Reiter's syndrome, rheumatic fever, rheumatoidarthritis, sarcoidosis, scleroderma, sepsis syndrome, Still's disease,shock, Sjogren's syndrome, skin inflammatory diseases, solid tumorgrowth and tumor invasion by secondary metastases, spondylitis, stroke,systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis,and Wegener's granulomatosis.

In another embodiment, the present invention provides novel compounds ofthe present invention for use in therapy.

In another embodiment, the present invention provides the use of novelcompounds of the present invention for the manufacture of a medicamentfor the treatment of a condition or disease mediated by MMPs, TNF,aggrecanase, or a combination thereof.

In another embodiment, the present invention provides a method fortreating inflammatory disorders, comprising: administering, to a mammalin need of such treatment, a therapeutically effective amount of one ofthe compounds of the present invention, in combination with one or moreadditional anti-inflammatory agents selected from selective COX-2inhibitors, interleukin-1 antagonists, dihydroorotate synthaseinhibitors, p38 MAP kinase inhibitors, TNF-α inhibitors, TNF-αsequestration agents, and methotrexate.

This invention also encompasses all combinations of preferred aspects ofthe invention noted herein. It is understood that any and allembodiments of the present invention may be taken in conjunction withany other embodiment to describe additional even more preferredembodiments of the present invention. It is also understood that eachand every element of any embodiment is intended to be a separatespecific embodiment. Furthermore, any elements of an embodiment aremeant to be combined with any and all other elements from any of theembodiments to describe additional embodiments.

Definitions

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Geometric isomers of double bonds such as olefins and C═N double bondscan also be present in the compounds described herein, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, and racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated. Allprocesses used to prepare compounds of the present invention andintermediates made therein are considered to be part of the presentinvention.

Preferably, the molecular weight of compounds of the present inventionis less than about 500, 550, 600, 650, 700, 750, 800, 850, or 900 gramsper mole. More preferably, the molecular weight is less than about 850grams per mole. Even more preferably, the molecular weight is less thanabout 750 grams per mole. Still more preferably, the molecular weight isless than about 700 grams per mole.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced. Keto substituents are not present on aromatic moieties. When aring system (e.g., carbocyclic or heterocyclic) is said to besubstituted with a carbonyl group or a double bond, it is intended thatthe carbonyl group or double bond be part (i.e., within) of the ring.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include tritium anddeuterium. Isotopes of carbon include C-13 and C-14.

The term “independently selected from”, “independently, at eachoccurrence” or similar language, means that the labeled R substitutiongroup may appear more than once and that each appearance may be adifferent atom or molecule found in the definition of that labeled Rsubstitution group. Thus if the labeled R^(a) substitution group appearfour times in a given permutation of Formula I, then each of thoselabeled R^(a) substitution groups may be a different group falling inthe definition of R^(a). Also, combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

In cases wherein there are amines on the compounds of this invention,these can be converted to amine N-oxides by treatment with MCPBA and orhydrogen peroxides to afford other compounds of this invention. Thus,all shown amines are considered to cover both the shown amine and itsN-oxide (N→O) derivative.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. C₁₋₁₀ alkyl (or alkylene),is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkylgroups. Examples of alkyl include, but are not limited to, methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, ands-pentyl. “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, and pentachloroethyl. “Alkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through an oxygen bridge. C₁₋₁₀ alkoxy, isintended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkoxygroups. Examples of alkoxy include, but are not limited to, methoxy,ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy,and s-pentoxy. “Cycloalkyl” is intended to include saturated ringgroups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C₃₋₇cycloalkyl, is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. “Alkenyl” or “alkenylene” is intended to include hydrocarbonchains of either a straight or branched configuration and one or moreunsaturated carbon-carbon bonds which may occur in any stable pointalong the chain, such as ethenyl and propenyl. C₂₋₁₀ alkenyl (oralkenylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkenyl groups. “Alkynyl” or “alkynylene” is intended to includehydrocarbon chains of either a straight or branched configuration andone or more triple carbon-carbon bonds which may occur in any stablepoint along the chain, such as ethynyl and propynyl. C₂₋₁₀ alkynyl (oralkynylene), is intended to include C₂, C₃, C₄, C₅, C₆, C₇, C₈, C₉, andC₁₀ alkynyl groups.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, and sulfate.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane,[2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl,and tetrahydronaphthyl.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S and including any bicyclic group inwhich any of the above-defined heterocyclic rings is fused to a benzenering. The nitrogen and sulfur heteroatoms may optionally be oxidized.The nitrogen atom may be substituted or unsubstituted (i.e., N or NRwherein R is H or another substituent, if defined). The heterocyclicring may be attached to its pendant group at any heteroatom or carbonatom that results in a stable structure. The heterocyclic ringsdescribed herein may be substituted on carbon or on a nitrogen atom ifthe resulting compound is stable. A nitrogen in the heterocycle mayoptionally be quaternized. It is preferred that when the total number ofS and O atoms in the heterocycle exceeds 1, then these heteroatoms arenot adjacent to one another. It is preferred that the total number of Sand O atoms in the heterocycle is not more than 1. As used herein, theterm “aromatic heterocyclic group” or “heteroaryl” is intended to mean astable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or10-membered bicyclic heterocyclic aromatic ring which consists of carbonatoms and 1, 2, 3, or 4 heterotams independently selected from the groupconsisting of N, O and S. It is to be noted that total number of S and Oatoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl,1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl,1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl,3,4-dihydro-2H-chromen-4-yl, imidazo[1,2-a]pyridinyl,imidazo[1,5-a]pyridinyl, and pyrazolo[1,5-a]pyridinyl. Also included arefused ring and spiro compounds containing, for example, the aboveheterocycles.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; and alkali or organic saltsof acidic residues such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.)the compounds of the present invention may be delivered in prodrug form.Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers that release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention or an amount of the combination ofcompounds claimed effective to inhibit a desired metalloprotease in amammal. The combination of compounds is preferably a synergisticcombination. Synergy, as described for example by Chou and Talalay, Adv.Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case,inhibition of the desired target) of the compounds when administered incombination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at suboptimal concentrations of thecompounds. Synergy can be in terms of lower cytotoxicity, increasedanti-inflammatory effect, or some other beneficial effect of thecombination compared with the individual components.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Compounds of formula I, wherein A is C(═O), B is O and L is O, can besynthesized using a variety of literature methods. For example, startingfrom diester 1 and urea (Scheme 1), the pyrimidinetrione 3 can beprepared by treatment with sodium methoxide in methanol (Reddy, D. B. etal. Heterocyclic Chem. 1993, 4, 55), magnesium methoxide generated insitu (Blicke, F. F. et al. J. Am. Chem. Soc. 1941, 63, 2945), orpotassium tert-butoxide in DMSO (Fraser, W. et al. J. Chem. Soc. PerkinTrans. I 1990, 3137). Alternatively, 3 can be synthesized from di-amide2 using diethyl carbonate, sodium hydroxide and ammonia (Shimo, K. etal. J. Org. Chem. 1959, 24, 19).

A series of pyrimidinetriones of formula 10 can be prepared following asequence outlined in Scheme 2. Deprotonation of malonate 4 with sodiumhydride and alkylation with (4-benzyloxyphenyl)alkyl halide 5 providedisubstituted-malonate 6. Following cleavage of benzyl ether, Z^(a)group is introduced by alkylation with 8 using a base such as cesiumcarbonate. Diester 9 is converted to pyrimidinetrione 10 followingconditions outlined in Scheme 1.

A series of pyrimidinetriones of formula 17 can be prepared following asequence outlined in Scheme 3. Carbomethoxylation of methyl(4-benzyloxyphenyl)acetate 11 is effected with sodium hydride and methylcarbonate. Alkylation of 12 with R¹—X results in disubstituted-malonate14. The benzyl group is replaced with CH₂-Z^(a) group by hydrogenationand alkylation. Diester 16 is converted to pyrimidinetrione 17 followingconditions outlined in Scheme 1.

Another series of pyrimidinetriones of formula I where R¹ is1-piperazinyl group can be synthesized following a sequence outlined inScheme 4. Starting from methyl (4-hydroxyphenyl)acetate 18, alkylationwith Z^(a)CH₂Cl (8) yields 19, which is converted to diester 20 usingsodium hydride and methyl carbonate. Diester 20 is then cyclized usingconditions described in Scheme 1. The resultant pyrimidinetrione isbrominated with bromine and the bromo group replaced in one-pot witht-butyl (1-piperazinyl)carboxylate to give 21. After removal of Bocgroup, the secondary amine of 22 is converted to tertiary amines byreductive animation, amides by reaction with anhydrides or acidchlorides, sulfonamides with sulfonyl chlorides, ureas with isocyanates,or carbamates with chloroformates.

A series of pyrimidinediones of formula 29 can be prepared following asequence outlined in Scheme 5. The starting aldehyde 24 can be preparedusing the synthesis reported U.S. Pat. No. 6,047,336. Oxidation ofaldehyde 24 with sodium chlorite gives carboxylic acid 25, which isconverted to urea 26 by Curtius rearrangement in the presence ofammonia. The benzyl group in 26 is replaced with CH₂Z^(a) group to give28. Treatment of 28 with cesium carbonate completes the synthesis ofpyrimidinedione 29.

Another series of pyrimidinediones of formula 43 can be synthesizedusing a sequence outlined in Scheme 6. O-Benzyl tyrosine methyl ester 30is converted to Schiff base 31 and allylated with LDA and allyl bromide.The imine is hydrolyzed with HCl and the resultant amine protected witha Boc group. The olefin moiety in 34 is degraded to aldehyde 35 andfurther oxidized to acid 36 with sodium chlorite. The acid 36 isactivated with isobutyl chloroformate and coupled with sodium azide toyield 37. Curtius rearrangement in the presence of ammonium hydroxidegives urea 38. Using the previously described conditions, the benzylgroup in 38 is replaced with CH₂Z^(a) and 40 is cyclized to givepyrimidinedione 41. The Boc group is then removed and the free amine in42 is functionalized with Q to complete the synthesis of 43.

A series of pyrimidinetriones of formula 50 can be prepared following asequence outlined in Scheme 7. TBS protection and reduction of4-hydroxycinnamic acid 44 provide alcohol 45. Conversion to bromide andcoupling with properly functionalized malonate 4 give diester 47. Thesilyl protecting can be removed with TBAF and the resultant phenol isfunctionalized with ClCH₂-Z^(a) (8). Compound 49 is converted topyrimidinetrione 50 following conditions outlined in Scheme 1.

One diastereomer of a compound of Formula I may display superioractivity compared with the others. Thus, the following stereochemistriesare considered to be a part of the present invention. Each stereoisomercan be synthesized selectively using the chemistry described in theprevious sections, or synthesized as a mixture and separated atintermediate or final compound stage by HPLC or chiral HPLC.

When required, separation of the racemic material can be achieved byHPLC using a chiral column or by a resolution using a resolving agentsuch as camphonic chloride as in Wilen, S. H. Tables of Resolving Agentsand Optical Resolutions 1972, 308 pp or using enantiomerically pureacids and bases. A chiral compound of Formula I may also be directlysynthesized using a chiral catalyst or a chiral ligand, e.g., Jacobsen,E. Acc. Chem. Res. 2000, 33, 421-431 or using other enantio- anddiastereo-selective reactions and reagents known to one skilled in theart of asymmetric synthesis.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “1×” foronce, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq”for equivalent or equivalents, “g” for gram or grams, “mg” for milligramor milligrams, “mL” for milliliter or milliliters, “¹H” for proton, “h”for hour or hours, “M” for molar, “min” for minute or minutes, “MHz” formegahertz, “MS” for mass spectroscopy, “NMR” for nuclear magneticresonance spectroscopy, “rt” for room temperature, “tlc” for thin layerchromatography, “v/v” for volume to volume ratio. “α”, “β”, “R” and “S”are stereochemical designations familiar to those skilled in the art.

Example 1 5-[4-(Benzyloxy)benzyl]-5-methyl-2,4,6(1H, 3H,5H)-pyrimidinetrione

(1a) A solution of dimethyl methylmalonate (1.00 g, 6.84 mmol) intetrahydrofuran (20 mL) was added to a suspension of 60 wt % sodiumhydride (410 mg, 1.5 eq) in tetrahydrofuran (20 mL) dropwise at rt over5 min. After 30 min at rt, 4-benzyloxybenzyl chloride (3.18 g, 2.0 eq)was added. The mixture was heated to reflux for 5 h, cooled to rt andquenched with saturated NaHCO₃ (10 mL). After dilution with ethylacetate (200 mL), the mixture was washed with water (2×10 mL), brine (10mL), dried (MgSO₄) and concentrated in vacuo. Purification of theresidue by silica gel column chromatography (ethyl acetate-hexanes, 1:9)provided the desired ester (1.60 g, 68%). MS found: (M+Na)⁺=365.

(1b) The product from reaction (1a) (150 mg, 0.438 mmol) and urea (53.0mg, 2.0 eq) were added to a solution of sodium methoxide (70.9 mg, 3.0eq) in methanol (5.0 mL). The resultant mixture was heated to reflux for24 h, cooled to rt, and adjusted to pH 5-6 with 1 N HCl, andconcentrated in vacuo. Purification by reverse phase HPLC (gradientelution, water/acetonitrile 70-30 to 10-90, 0.1% TFA) provided the titlebarbituric acid (75.0 mg, 51%). MS found: (2M−H)⁻=675.

Example 25-Methyl-5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4,6(1H, 3H,5H)-pyrimidinetrione trifluoroacetate

(2a) The product from reaction (1a) (1.50 g, 4.38 mmol) and 20 wt %palladium hydroxide on carbon (300 mg, 0.2 eq) in methanol (50 mL) werestirred under balloon pressure hydrogen for 2 h. The mixture was purgedwith nitrogen, filtered through a plug of Celite®. The filter cake waswashed with excess methanol. The filtrate was concentrated to providethe desired phenol (1.10 g, 100%). MS found: (2M−H)⁻=503.

(2b) Cesium carbonate (213 mg, 1.1 eq) was added to a solution of thephenol from reaction (2a) (150 mg, 0.595 mmol) and4-(chloromethyl)-2-methylquinoline (136 mg, 1.2 eq) in DMSO (4 mL).After 24 h at rt, saturated NaHCO₃ (5 mL)and ethyl acetate (100 mL) wereadded. The mixture was washed with water (2×5 mL), brine (5 mL), dried(MgSO₄) and concentrated in vacuo. Purification of the residue by silicagel column chromatography (ethyl acetate-hexanes, 5:5) yielded thedesired ether (220 mg, 91%). MS found: (M+H)⁺=408.

(2c) Magnesium turnings (18.0 mg, 3.0 eq) was added to dry methanol (4mL). The resultant mixture was heated to reflux until the metal wasdissolved (1 h) and cooled to rt. The product from reaction (2b) (100mg, 0.245 mmol) and urea (29.4 mg, 2.0 eq) were added. After stirring atreflux for 5 h, most of the solvent was removed by distillation. Theresultant paste was kept at 85-90° C. for 24 h, cooled to rt, andadjusted to pH 3-4 with 1 N HCl. Purification by reverse phase HPLC(gradient elution, water/acetonitrile 75-25 to 25-75, 0.1% TFA) providedthe title barbituric acid (80.0 mg, 63%). MS found: (M+H)⁺=404.

Example 45-Methyl-5-(2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}ethyl)-2,4,6(1H,3H, 5H)-pyrimidinetrione trifluoroacetate

(4a) A solution of methyl (4-benzyloxyphenyl)acetate (2.00 g, 7.80 mmol)in tetrahydrofuran (50 mL) was treated with 2.0 M solution of lithiumborohydride in tetrahydrofuran (11.7 mL, 3.0 eq) at rt and stirred for24 h. The mixture was adjusted to pH 5-6 with 1 N HCl, diluted withethyl acetate (300 mL), washed with water (10 mL), brine (10 mL), dried(MgSO₄) and concentrated in vacuo to provide the desired alcohol (1.68g, 95%). MS found: (M+H)⁺=229.

(4b) A solution of triphenylphosphine (1.90 g, 1.1 eq), imidazole (491mg, 1.1 eq) and carbon tetrabromide (2.40 g, 1.1 eq) in dichloromethane(50 mL) was added to the solution of the alcohol from reaction (4a)(1.50 g, 6.57 mmol) in dichloromethane (50 mL) at 0° C. After 30 min at0° C., the mixture was concentrated and purified by silica gel columnchromatography (ethyl acetate-hexanes, 5:95) to provide the desiredbromide (1.70 g, 89%). MS found: (M+H)⁺=292.

(4c) Using a procedure analogous to reaction (1a), dimethylmethylmalonate (700 mg, 4.79 mmol) was treated with the bromide fromreaction (4b) (1.53 g, 1.1 eq) to provide the desired ester (700 mg,41%). MS found: (M+Na)⁺=379.

(4d) Using an analogous procedure to (2a), the product from reaction(4c) (300 mg, 0.842 mmol) was converted to the desired phenol (220 mg,100%). MS found: (2M−H)⁻=532.

(4e) Using a procedure analogous to reaction (2b), the product fromreaction (4d) (120 mg, 0.451 mmol) was treated with4-(chloromethyl)-2-methylquinoline (103 mg, 1.2 eq) to provide thedesired ether (170 mg, 95%). MS found: (M+H)⁺=422.

(4f) Using an analogous procedure to (2c) the product from reaction (4e)(75.0 mg, 0.178 mmol) was converted to the title barbituric acid (45.0mg, 60%). MS found: (M+H)⁺=418.

Example 5 tert-Butyl5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4,6-trioxohexahydro-5-pyrimidinylcarbamatetrifluoroacetate

(5a) Dimethyl aminomalonate hydrochloride salt (2.00 g, 10.9 mmol) wastreated with di-tert-butyl dicarbonate (2.50 g, 1.05 eq) andN,N-diisopropylethylamine (4.20 mL, 2.2 eq) in dichloromethane (50 mL)at rt and stirred for 24 h. The mixture was quenched with saturatedNaHCO₃ (20 mL), diluted with ethyl acetate (300 mL), washed with water(2×15 mL), brine (15 mL), dried (MgSO₄) and concentrated in vacuo.Purification of the residue by silica gel column chromatography (ethylacetate-hexanes, 2:8) yielded the desired ester (2.50 g, 94%). MS found:(M+CH₃CN+H)⁺=289.

(5b) The product from reaction (5a) (700 mg, 0.283 mmol) was treatedwith 60 wt % sodium hydride (125 mg, 1.1 eq) in N,N-dimethylformamide(10 mL) at rt. After 30 min at rt, 4-benzyloxybenzyl chloride (790 mg,1.2 eq) was added. The mixture was stirred at rt for 2 h, quenched withsaturated NaHCO₃ (10 mL), diluted with ethyl acetate (200 mL), washedwith water (2×20 mL), brine (20 mL), dried (MgSO₄) and concentrated invacuo. Purification of the residue by silica gel column chromatography(ethyl acetate-hexanes, 3:7) gave the desired ester (670 mg, 25%). MSfound: (M+Na)⁺=466.

(5c) Using an analogous procedure to (2a) the product from reaction (5b)(320 mg, 0.721 mmol) was converted to the desired phenol (200 mg, 79%).MS found: (M−H)⁻=352.

(5d) Using a procedure analogous to reaction (2b), the product fromreaction (5c) (120 mg, 0.339 mmol) was treated with4-(chloromethyl)-2-methylquinoline (78.0 mg, 1.2 eq) to provide thedesired ether (150 mg, 87%). MS found: (M+H)⁺=509.

(5e) In an analogous procedure to (2c) the product from reaction (5d)(140 mg, 0.275 mmol) was converted to the title barbituric acid (100 mg,72%). MS found: (M+H)⁺=505.

Example 6

5-Amino-5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4,6(1H, 3H,5H)-pyrimidinetrione bis(trifluoroacetate)

The product from reaction (5e) (80.0 mg, 0.159 mmol) was treated withtrifluoacetic acid (2.0 mL) in dichloromethane (2.0 mL). After 1 h atrt, the mixture was concentrated in vacuo to provide the titlebarbituric acid (100 mg, 100%). MS found: (M+H)⁺=405.

Example 7

5-Methyl-5-((2E)-3-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-propenyl)-2,4,6(1H,3H, 5H)-pyrimidinetrione

(7a) TBSCl (15.89 g, 2.1 eq) was added to a solution of4-hydroxycinnamic acid (8.24 g, 50 mmol) and imidazole (10.25 g, 3 eq)in DMF (100 mL) at rt. The resulting solution was stirred for 48 h. DMFwas then removed by high-vac rotary evaporator at 60° C. The residue wasdissolved in ether (150 mL), washed with 5% citric acid (150 mL), water(150 mL) and brine (150 mL). The ether solution was dried (MgSO₄) andconcentrated to give a white solid (15.74 g). This TBS ester was used inthe next step without further purification.

(7b) To a ether (100 mL) slurry of the ester (15.74 g, 40 mmol) from(7a) at 0° C. was added DIBAL (1M toluene solution, 100 mL, 2.5 eq)dropwise in 1 h. The reaction was stirred at 0° C. for another 1 h thenquenched by slowly adding Rochelle's solution (100 mL) at 0° C. Themixture was extracted with ether (2×350 mL). The combined ether phasewas washed with brine (350 mL), dried (MgSO₄), filtered through a shortbed of Celite® and concentrated. The crude product was purified by flashcolumn chromatography (15% ethyl acetate-hexane) to yield the desiredalcohol as a colorless oil (4.68 g, 35% for 2 steps). ¹H NMR wasconsistent with literature data (Young, S. D.; Payne, L. S.; Thompson,W. J.; Gaffin, N.; Lyle, T. A.; Britcher, S. F.; Graham, S. L.; Schultz,T. H.; Deana, A. A.; Darke, P. L.; Zugay, J.; Schleif, W. A.; Quintero,J. C.; Emini, E. A.; Anderson, P. S.; Huff, J. R. J. Med. Chem. 1992,35, 1702-1709).

(7c) The alcohol from (7b) (2.24 g, 8.5 mmol) in ether (35 mL) wastreated with PBr₃ (0.88 mL, 1.1 eq) and stirred for 20 min at 0° C.After the reaction was complete, the mixture was poured into saturatedNaHCO₃ (100 mL), diluted with hexanes. The hexanes layer was washed withbrine, dried (MgSO₄), filtered through a short bed of silica gel andconcentrated to give the bromide as a brown oil (1.37 g, 49%). ¹H NMRwas consistent with literature data.

(7d) NaH (60% in mineral oil, 0.3 g, 1.8 eq) was added to a THF (20 mL)solution of dimethyl methylmalonate (0.73 g, 1.2 eq) at 0° C. Themixture was stirred for an additional 10 min, then a THF (20 mL)solution of the bromide (1.37 g, 4.19 mmol) from (7c) was added at 0° C.The mixture was stirred at rt overnight, quenched by slowly addingwater, and extracted with ethyl acetate (2×100 mL), dried (MgSO₄),filtered and purified by flash column chromatography (10% ethylacetate-hexane) to yield the unsaturated TBS ether as a colorless oil(0.85 g, 52%). MS Found: (M+H)⁺=393.

(7e) To a THF (1 mL) solution of the unsaturated TBS ether (0.1 g, 0.25mmol) from (7d) was added TBAF (1 M THF solution, 0.5 mL, 2 eq) at rt.After 20 min, TLC (10% ethyl acetate-hexanes) showed the reaction wascomplete. The mixture was concentrated and purified by flash columnchromatography (25% ethyl acetate-hexane) to yield the unsaturatedphenol as a colorless oil (0.071 g, 99%). MS Found: (M+H)⁺=279.

(7f) The unsaturated phenol (71 mg, 0.26 mmol) from (7e) was mixed with4-chloromethyl-2-methylquinoline (50 mg, 1 eq) and cesium carbonate (169mg, 2 eq) in DMF (1 mL) and stirred at rt overnight. After the reactionwas complete, DMF was removed by high-vac rotary evaporator at 60° C.The residue was purified by flash column chromatography (40% ethylacetate-hexane) to yield the unsaturated quinoline ether as a colorlessoil (95 mg, 84%). MS Found: (M+H)⁺=434.

(7g) Magnesium turnings (24 mg, 4.2 eq) was heated in reflux methanol (3mL) until the metal disappeared. To the resulting white cloudy solutionof magnesium methoxide was added urea (40 mg, 2.8 eq) and theunsaturated quinoline ether (105 mg in 0.5 mL CH₂Cl₂, 0.24 mmol) from(7f). The mixture was refluxed for 48 h, concentrated and purified bysilica gel chromatography (75% ethyl acetate-hexane) to give thebarbituric acid as a white solid (19 mg, 19%). MS Found: (M+H)⁺=430.

Example 85-Methyl-5-(3-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}propyl)-2,4,6(1H,3H, 5H)-pyrimidinetrione

(8a) The unsaturated TBS ether (0.32 g, 0.82 mmol) from (7d) andpalladium on carbon (0.03 g) in ethyl acetate-methanol (1:1, 2 mL) wasstirred under balloon pressure hydrogen for 1.5 h. The mixture was thenfiltered and the filtrate concentrated to give the saturated TBS etheras a colorless oil (0.28 g, 88%). MS Found: (M+H)⁺=395.

(8b) Following an analogous procedure to (7e) the TBS ether fromreaction (8a) (140 mg, 0.275 mmol) was converted to the phenol as acolorless oil (0.19 g, 94%). MS Found: (M+H)⁺=281.

(8c) Following an analogous procedure to (7f) the phenol (157 mg, 0.56mmol) from (8b) was converted to the quinoline ether as a colorless oil(149 mg, 61%). MS Found: (M+H)⁺=436.

(8d) Following an analogous procedure to (7g) the quinoline ether (149mg in 0.5 mL CH₂Cl₂ 0.34 mmol) from (8c) was converted to the titlebarbituric acid as a white solid (5.3 mg, 4%). MS Found: (M+H)⁺=432.

Example 9 5-[4-(Benzyloxy)phenyl]-5-methyl-2,4,6(1H, 3H,5H)-pyrimidinetrione

(9a) A solution of methyl [4-(benzyloxy)phenyl]acetate (3.00 g, 11.7mmol) in tetrahydrofuran (20 mL) was added dropwise to a suspension of60 wt % sodium hydride (1.08 g, 2.3 eq) in tetrahydrofuran (100 mL) atrt over 10 min. After 30 min at rt, dimethyl carbonate (3.94 mL, 4.0 eq)was added. After 24 h at reflux, the mixture was cooled to rt, quenchedwith 1 N HCl (70 mL), diluted with ethyl acetate (400 mL), washed withwater (20 mL, 2 times), brine (20 mL), dried (MgSO₄) and concentrated invacuo. Purification of the residue by silica gel column chromatography(ethyl acetate-hexanes, 2:8) yielded the desired dimethyl ester (2.95 g,80%). MS found: (M+CH₃CN+Na)⁺=378.

(9b) The dimethyl ester from reaction (9a) (1.50 g, 4.77 mmol) and urea(573 mg, 2.0 eq) were added to a solution of sodium methoxide (773 mg,3.0 eq) in methanol (20 mL). The resultant mixture was heated to refluxfor 24 h, cooled to rt, and adjusted to pH 5-6 with 1 N HCl. The whiteprecipitate was filtered and washed with water (2×5 mL), ethyl acetate(2×5 mL), and dried under vacuum to provide the desired barbituric acid(900 mg, 61%). MS found: (2M−H)⁻=619.

(9c) The barbituric acid from reaction (9b) (150 mg, 0.483 mmol) intetrahydrofuran (15 mL) was treated with sodium hydride (58.0 mg, 3.0eq) at rt. The resultant mixture was heated to reflux for 30 min andcooled to rt. After addition of iodomethane (0.300 mL, 1.0 eq), themixture was heated to reflux for 5 h, cooled to rt and quenched with 1 NHCl to pH 3-4. Purification by reverse phase HPLC (gradient elution,water/acetonitrile 60-40 to 35-65, 0.1% TFA) provided the titlebarbituric acid (10.0 mg, 6.5%). MS found: (M−H)⁻=323.

Example 105-Methyl-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H, 3H,5H)-pyrimidinetrione

(10a) A solution of the dimethyl ester from reaction (9a) (2.00 g, 6.36mmol) in tetrahydrofuran (10 mL) was added dropwise to a suspension of60 wt % sodium hydride (305 mg, 1.2 eq) in tetrahydrofuran (50 mL) at rtover 5 min. After 30 min at rt, iodomethane (0.80 mL, 2.0 eq) was added.The mixture was heated to reflux for 3 h, cooled to rt, and quenchedwith saturated NaHCO₃ (20 mL). After addition of ethyl acetate (300 mL),the mixture was washed with water (20 mL), brine (20 mL), dried (MgSO₄)and concentrated in vacuo. Purification of the residue by silica gelcolumn chromatography (ethyl acetate-hexanes, 1:9) gave the desiredester (1.70 g, 81%). MS found: (M+H)⁺=329.

(10b) The ester from reaction (10a) (1.00 g, 3.04 mmol) and 20 wt %palladium hydroxide on carbon (200 mg, 0.2 eq) in methanol (30 mL) wasstirred under balloon pressure hydrogen for 2 h. The mixture was purgedwith nitrogen, filtered through a plug of Celite®. The filter cake waswashed with methanol until free of product. The filtrate wasconcentrated to provide the desired phenol (730 mg, 100%).(M+CH₃CN+H)⁺=280.

(10c) Cesium carbonate (1.05 g, 1.1 eq) was added to a solution of thephenol form reaction (10b) (700 mg, 2.94 mmol) and4-(chloromethyl)-2-methylquinoline (673 mg, 2.0 eq) in DMSO (15 mL) atrt. After 24 h at rt, saturated NaHCO₃ (10 mL) and ethyl acetate (250mL) were added. The mixture was washed with water (2×10 mL), brine (10mL), dried (MgSO₄) and concentrated in vacuo. Purification of theresidue by silica gel column chromatography (ethyl acetate-hexanes, 5:5)yielded the desired ether (1.10 g, 95%). MS found: (M+H)⁺=394.

(10d) In an analogous procedure to (9b) the product from reaction (210)(150 mg, 0.381 mmol) was converted to the title barbituric acid.Purification by silica gel column chromatography(methanol-dichloromethane, 5:95) provided the desired barbituric acid(30.0 mg, 20%). MS found: (M+H)⁺=390.

Example 115-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-5-(1-piperidinyl)-2,4,6(1H,3H, 5H)-pyrimidinetrione bis(trifluoroacetate)

(11a) Using a procedure analogous to reaction (10c), methyl4-hydroxyphenylacetate (10.0 g, 60.2 mmol) was treated with4-(chloromethyl)-2-metylquinoline hydrochloride salt (15.1 g, 1.1 eq) toprovide the desired ether (15.0 g, 78%). MS found: (M+H)⁺=322.

(11b) In an analogous procedure to (9a) the product from reaction (11a)(15.0 g, 46.7 mmol) was converted to the desired dimethyl ester (10.0 g,55%). MS found: (M+H)⁺=380.

(11c) A solution of The product from reaction (11b) (200 mg, 0.527 mmol)and urea (95.0 mg, 3.0 eq) in methanol (2.0 mL) was treated with 0.5 Msodium methoxide in methanol (1.30 mL, 1.2 eq). The resultant mixturewas heated to reflux for 3 h and cooled to 10-15° C. Piperidine (0.11mL, 2.0 eq), potassium carbonate (145 mg, 2.0 eq) and bromine (0.06 mL,2.2 eq) were sequentially. The mixture was slowly warmed to rt over 2 h,heated to reflux for 1 h, cooled to rt, and adjusted to pH 5-6 with 1 NHCl. Following addition of ethyl acetate (150 mL), the mixture waswashed with water (10 mL) and brine (10 mL), dried (MgSO₄) andconcentrated in vacuo. Purification by reverse phase HPLC (gradientelution, water/acetonitrile 80-20 to 10-90, 0.1% TFA) provided the titlebarbituric acid (130 mg, 83%). MS found: (M+H)⁺=459.

Example 125-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-5-(4-morpholinyl)-2,4,6(1H,3H, 5H)-pyrimidinetrione bis(trifluoroacetate)

Using a procedure analogous to reaction (11c), the product from reaction(11b) (200 mg, 0.527 mmol) was treated with morpholine (0.09 mL, 2.0 eq)to provide the title barbituric acid (15.0 mg, 4.1%). MS found:(M+H)⁺=461.

Example 13 tert-Butyl4-(5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6-trioxohexahydro-5-pyrimidinyl)-1-piperazinecarboxylatebis(trifluoroacetate)

Using a procedure analogous to reaction (11c), the product from reaction(11b) (178 mg, 0.470 mmol) was treated with 1-Boc-piperazine (175 mg,2.0 eq) to provide the title barbituric acid (125 mg, 34%). MS found:(M+H)⁺=560.

Example 145-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-5-(1-piperazinyl)-2,4,6(1H,3H, 5H)-pyrimidinetrione tris(trifluoroacetate)

The product from example 13 (50 mg, 0.0635 mmol) was treated withtrifluoacetic acid (2.0 mL) in dichloromethane (2.0 mL) at rt for 1 h.The mixture was concentrated in vacuo to provide the title barbituricacid (50.8 mg, 100%). MS found: (M+H)⁺=460.

Example 155-(4-Methyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H, 5H)-pyrimidinetrione tris(trifluoroacetate)

N,N-diisopropylethylamine (0.16 mL, 6.0 eq) and sodiumtriacetoxyborohydride (127 mg, 4.0 eq) were added to a solution of theproduct from example 14 (120 mg, 0.150 mmol) and 37 wt % formaldehyde(24.0 mg, 2.0 eq) in 1,2-dichloroethane (4.0 mL) at rt. After 24 h atrt, saturated NaHCO₃ (5 mL) and ethyl acetate (100 mL) were added. Themixture was washed with water (2×5 mL), brine (5 mL), dried (MgSO₄) andconcentrated in vacuo. Purification by reverse phase HPLC (gradientelution, water/acetonitrile 80-20 to 10-90, 0.1% TFA) provided the titlebarbituric acid (30.0 mg, 25%). MS found: (M+H)⁺=474.

Example 165-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(2-phenylethyl)-1-piperazinyl]-2,4,6(1H,3H, 5H)-pyrimidinetrione tris(trifluoroacetate)

Using a procedure analogous to Example 15, the product from example 14(100 mg, 0.125 mmol) was treated with phenylacetaldehyde (22.5 mg, 1.5eq) to provide the title barbituric acid (45.0 mg, 40%). MS found:(M+H)⁺=564.

Example 175-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-5-(4-neopentyl-1-piperazinyl)-2,4,6(1H,3H, 5H)-pyrimidinetrione tris(trifluoroacetate)

Using a procedure analogous to Example 15, the product from example 14(100 mg, 0.125 mmol) was treated with trimethylacetaldehyde (21.5 mg,2.0 eq) to provide the title barbituric acid (6.0 mg, 5.5%). MS found:(M+H)⁺=530.

Example 185-(4-Isopropyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H, 5H)-pyrimidinetrione tris(trifluoroacetate)

Using a procedure analogous to Example 15, the product from example 14(100 mg, 0.125 mmol) was treated with acetone (0.13 mL, 10 eq) toprovide the title barbituric acid (15.0 mg, 14%). MS found: (M+H)⁺=502.

Example 195-(4-Hexyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H, 5H)-pyrimidinetrione tris(trifluoroacetate)

Using a procedure analogous to Example 15, the product from example 14(100 mg, 0.125 mmol) was treated with hexanal (18.8 mg, 1.5 eq) toprovide the title barbituric acid (70.0 mg, 63%). MS found: (M+H)⁺=544.

Example 205-(4-Benzyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H, 5H)-pyrimidinetrione tris(trifluoroacetate)

Using a procedure analogous to Example 15, the product from example 14(120 mg, 0.150 mmol) was treated with benzaldehyde (31.8 mg, 2.0 eq) toprovide the title barbituric acid (35.0 mg, 26%). MS found: (M+H)⁺=550.

Example 215-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(3-phenylpropyl)-1-piperazinyl]-2,4,6(1H,3H, 5H)-pyrimidinetrione tris(trifluoroacetate)

Using a procedure analogous to Example 15, the product from example 14(100 mg, 0.125 mmol) was treated with 3-phenylpropionaldehyde (25.1 mg,1.5 eq) to provide the title barbituric acid (80.0 mg, 70%). MS found:(M+H)⁺=578.

Example 225-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(4-nitrophenyl)-1-piperazinyl]-2,4,6(1H,3H, 5H)-pyrimidinetrione tris(trifluoroacetate)

Using a procedure analogous to reaction (11c), the product from reaction(11b) (200 mg, 0.527 mmol) was treated with 1-(4-nitrophenyl)piperazine(218 mg, 2.0 eq) to provide the title barbituric acid (5.0 mg, 1.0%). MSfound: (M+H)⁺=581.

Example 235-[4-(2-Hydroxyethyl)-1-piperazinyl]-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H, 5H)-pyrimidinetrione tris(trifluoroacetate)

Using a procedure analogous to reaction (11c), the product from reaction(11b) (400 mg, 1.05 mmol) was treated with 1-(2-hydroxyethyl)piperazine(273 mg, 2.0 eq) to provide the title barbituric acid (35.0 mg, 3.9%).MS found: (M+H)⁺=504.

Example 244-[4-(5-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-2,4,6-trioxohexahydro-5-pyrimidinyl)-1-piperazinyl]butanoicacid tris(trifluoroacetate)

Using a procedure analogous to Example 15, the product from example 14(100 mg, 0.125 mmol) was treated with succinic semialdehyde (76.6 mg,6.0 eq) to provide the title barbituric acid (50.0 mg, 45%). MS found:(M+H)⁺=546.

Example 25N-Methyl-4-[4-(5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6-trioxohexahydro-5-pyrimidinyl)-1-piperazinyl]butanamidetris(trifluoroacetate)

N,N-diisopropylethylamine (0.04 mL, 7.0 eq) and BOP reagent (14.0 mg,1.1 eq) were added to a solution of the product from Example 24 (25.0mg, 0.0280 mmol) and methylamine hydrochloride (4.0 mg, 2.0 eq) inN,N-dimethylformamide (1.0 mL) at rt. After 1 h at rt, the mixture wasquenched with water (1.0 mL) and purified by reverse phase HPLC(gradient elution, water/acetonitrile 90-10 to 10-90, 0.1% TFA) toprovide the title barbituric acid (6.0 mg, 24%). MS found: (M+H)⁺=559.

Example 265-(4-Acetyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H, 5H)-pyrimidinetrione bis(trifluoroacetate)

The product from Example 14 (120 mg, 0.150 mmol) was treated withN,N-diisopropylethylamine (0.13 mL, 5.0 eq) and acetic anhydride (30.6mg, 2.0 eq) in dichloromethane (5 mL) at rt. After 1 h at rt, saturatedNaHCO₃ (5 mL) and ethyl acetate (100 mL) were added. The mixture waswashed with water (2×5 mL), brine (5 mL), dried (MgSO₄) and concentratedin vacuo. Purification by reverse phase HPLC (gradient elution,water/acetonitrile 80-20 to 20-80, 0.1% TFA) provided the titlebarbituric acid (75.4 mg, 69%). MS found: (M+H)⁺=502.

Example 275-[4-(2,2-Dimethylpropanoyl)-1-piperazinyl]-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H, 5H)-pyrimidinetrione bis(trifluoroacetate)

Using a procedure analogous to Example 26, the product from Example 14(120 mg, 0.150 mmol) was treated with pivaloyl chloride (21.7 mg, 1.2eq) to provide the title barbituric acid (45.0 mg, 40%). MS found:(M+H)⁺=544.

Example 285-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(methylsulfonyl)-1-piperazinyl]-2,4,6(1H,3H, 5H)-pyrimidinetrione bis(trifluoroacetate)

Using a procedure analogous to Example 26, the product from Example 14(120 mg, 0.150 mmol) was treated with methanesulfonyl chloride (24.0 mg,1.4 eq) to provide the title barbituric acid (42.0 mg, 37%). MS found:(M+H)⁺=538.

Example 29 5-[4-(Benzyloxy)phenyl]-5-methyldihydro-2,4(1H,3H)-pyrimidinedione

(29a) A solution of sodium chlorite (1.21 g, 1.5 eq) and potassiumdihydrogenphosphate (1.32 g, 1.5 eq) in water (18 mL) was added dropwiseto a mixture of methyl 2-[4-(benzyloxy)phenyl]-2-methyl-4-oxobutanoate(2.00 g, 6.40 mmol, prepared following procedures reported in patentapplication U.S. Pat. No. 6,057,336), 2-methyl-2-butene (8 mL) andtert-butyl alcohol (8 mL) in tetrahydrofuran (8 mL) over 5 min at rt.After 30 min at rt, 1 N HCl was added to adjust the pH to 2-3. Themixture was the diluted with ethyl acetate (200 mL), washed with water(2×10 mL), brine (10 mL), dried (MgSO₄) and concentrated in vacuo toprovide the desired acid (1.90 g, 91%). MS found: (M+Na)⁺=351.

(29b) Triethylamine (1.45 mL, 2.0 eq) and diphenylphosphoryl azide (1.34mL, 1.2 eq) were added to the acid from reaction (29a) (1.70 g, 5.18mmol) in benzene (40 mL) at rt. The mixture was heated to reflux for 1 hand cooled to rt. Ammonia gas was bubbled into the solution for 5 min.After stirring for 24 h at rt, ethyl acetate (200 mL) was added. Themixture was washed with water (2×10 mL), brine (10 mL), dried (MgSO₄)and concentrated in vacuo. Purification of the residue bycrystallization (methanol-ethyl acetate) provided the desired urea (1.50g, 85%). MS found: (M+H)⁺=343.

(29c) The urea from reaction (29b) (100 mg, 0.292 mmol) was treated with1 N sodium hydroxide (1.2 mL, 4.0 eq) in methanol (1.2 mL) at rt. After24 h at rt, the mixture was adjusted to pH 2-3 with 1 N HCl. The whiteprecipitate was washed with water (2 mL) and dried under vacuum toprovide the title compound (60.0 mg, 66%). MS found: (2M−H)⁻=619.

Example 305-Methyl-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}dihydro-2,4(1H,3H)-pyrimidinedione trifluoroacetate

(30a) In an analogous procedure to reaction (10b) the product fromreaction (29c) (200 mg, 0.584 mmol) was converted to the desired phenol(147 mg, 100%). MS found: (M+H)⁺=253.

(30b) Using a procedure analogous to reaction (10c), the phenol fromreaction (30a) (130 mg, 0.515 mmol) was reacted with4-(chloromethyl)-2-methylquinoline (108 mg, 1.1 eq). The mixture waspurified by reverse phase HPLC (gradient elution, water/acetonitrile80-20 to 30-70, 0.1% TFA) provided the title compound (70.0 mg, 28%). MSfound: (M+H)⁺=376.

Example 31 tert-Butyl(5S)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4-dioxohexahydro-5-pyrimidinylcarbamatetrifluoroacetate

(31a) In an analogous procedure to reaction (29a), ethyl(2R)-2-[4-(benzyloxy)phenyl]-2-[(tert-butoxycarbonyl)amino]-4-oxobutanoate(2.85 g, 6.43 mmol, prepared following procedures reported in U.S. Pat.No. 6,057,336) was converted to the desired acid (2.85 g, 100%). MSfound: (M+Na)⁺=466.

(31b) Isobutyl chloroformate (1.20 mL, 2.0 eq) was added to the acidfrom reaction (31a) (2.00 g, 4.51 mmol) and triethylamine (1.60 mL, 2.5eq) in tetrahydrofuran (40 mL) at 0° C. After 30 min at thattemperature, a solution of sodium azide (6.00 g, 20 eq) in water (20 mL)was added, and the resultant mixture was kept at 0° C. for 1 h. Afteraddition of ethyl acetate (300 mL), the mixture was washed with water(10 mL), brine (20 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was dissolved in benzene (80 mL) and heated to reflux for 1 hand then cooled to rt. Ammonium hydroxide in water (28 wt %, 20 mL) wasadded. After 1 h at rt, the mixture was diluted with ethyl acetate (300mL), washed with water (20 mL), brine (20 mL), dried (MgSO₄) andconcentrated in vacuo. Purification of the residue by silica gel columnchromatography (ethyl acetate-hexanes, 7:3) yielded the desired urea(1.60 g, 78%). MS found: (M+H)⁺=458.

(31c) In an analogous procedure to reaction (10b), the urea fromreaction (31b) (1.60 g, 3.36 mmol) was converted to the desired phenol(1.22 g, 100%). MS found: (M+H)⁺=368.

(31d) Using a procedure analogous to reaction (10c), the phenol fromreaction (31c) (800 mg, 2.18 mmol) was reacted with4-(chloromethyl)-2-methylquinoline hydrochloride (545 mg, 1.1 eq). Themixture was purified by reverse phase HPLC (gradient elution,water/acetonitrile 75-25 to 10-90, 0.1% TFA) to provide the titlecompound (600 mg, 47%). MS found: (M+H)⁺=477.

Example 32(5S)-5-Amino-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}dihydro-2,4(1H,3H)-pyrimidinedione bis(trifluoroacetate)

In an analogous procedure to Example 14, the product from Example 31(550 mg, 0.932 mmol) was converted to the title compound (563 mg, 100%).MS found: (M+H)⁺=377.

Example 345-{4-[(2-Methyl-4-quinolinyl)methoxy]phenyl}-5-(4-piperidinyl)dihydro-2,4(1H,3H)-pyrimidinedione bis(trifluoroacetate)

In an analogous procedure to Example 14, the product from reaction (33g)(60.0 mg, 0.110 mmol) was converted to the title compound (74.0 mg,100%). MS found: (M+H)⁺=445.

Example 35 tert-Butyl5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4-dioxohexahydro-5-pyrimidinylcarbamatetrifluoroacetate

(35a) A mixture of H-Tyr(Bzl)-OMe (5.02 g, 15.6 mmol) and benzophenoneimine (2.91 g, 1.0 eq.) in dichloromethane (100 mL) was stirred at rtunder nitrogen for 24 h. The reaction was diluted with dichloromethane(100 mL), washed with water (2×100 mL). The organic layer was dried(MgSO₄) and concentrated to provide the desired imine (7.0 g). MS found:(M+H)⁺=450.

(35b) To a −78° C. solution of diisopropylamine (1.82 mL, 12.98 mmol) intetrahydrofuran (60 mL) was added n-butyllithium (8.10 mL, 1.6 M inhexanes, 12.96 mmol). The mixture stirred at 0° C. for 30 min, thencooled to −78° C. To this LDA solution was added dropwise the imine (5.3g, 11.8 mmol) from reaction (35a) in tetrahydrofuran (20 mL). After 30min at −78° C., 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.85mL, 2 eq.) was added, followed by allyl bromide (2.2 mL, 2.2 eq.) over10 min. The resulting mixture was stirred at −78° C. for 1.5 h, −10° C.to 0° C. for 2.5 h, then at ambient temperature for 30 min beforequenched with saturated ammonium chloride and extracted with ethylacetate (2×200 mL). The combined extracts were washed with brine, dried(MgSO₄) and concentrated in vacuo. Purification using silica gelchromatography (10% then 20% ethyl acetate/hexane) provided the desiredproduct with minor impurity (1.5 g). This material was taken to the nextstep without further purification. MS found: (M+H)⁺=490.

(35c) A mixture of the product (1.5 g) from reaction (35b) and 1 Nhydrochloric acid (20 mL) in ether was stirred at rt for 24 h. The etherlayer was separated. The aqueous was extracted with ether (40 mL). Thecombined ether layers were concentrated to provide the aminehydrochloride (1.0 g). This crude material was taken to the next stepwithout purification. MS found: (M+H)⁺=326.

(35d) To a mixture of the amine (1.0 g) from reaction (35c) and sodiumbicarbonate (0.9 g, 10.74 mmol) in dimethylformamide/tert-butyl alcohol(1:1, 5 mL) was added di-tert-butyl dicarbonate (1.7 g, 7.79 mmol) indimethylformamide/tert-butyl alcohol (1:1, 2 mL). The mixture was heatedat 60° C. for 2 h before quenched with aqueous ammonium chloride andextracted with ethyl acetate (2×100 mL). The combined extracts werewashed with brine, dried (MgSO₄) and concentrated. Purification usingsilica gel chromatography (10% ethyl acetate/hexane) provided thedesired N-Boc product (0.5 g, 10% for 3 steps). MS found: (M+Na)⁺=448.

(35e) Into a −78° C. solution of the product from reaction (35d) (0.56g, 1.32 mmol) in dichloromethane (20 mL) was bubbled O₃ until thereaction mixture turned blue. Triphenylphosphine (0.42 g, 1.2 eq.) wasadded. The mixture was stirred at ambient temperature for 1 h and thenconcentrated in vacuo. The residue was purified by silica gelchromatography (20% then 40% ethyl acetate/hexane) to provide thedesired aldehyde (0.51 g). MS found: (M−H)⁻=426.

(35f) To the aldehyde (0.51 g, 1.2 mmol) from reaction (35e) in2-methyl-2-butene (2 mL), tert-butyl alcohol (2 mL) and tetrahydrofuran(2 mL) was added dropwise a solution of NaClO₂ (0.25 g, 1.5 eq.) andKH₂PO₄ (0.27 g, 1.5 eq.) in water (5 mL). After 30 min at rt, thereaction mixture was acidified with 1 N hydrochloric acid to pH 2-3, andextracted with ethyl acetate (10 mL). The extract was washed with water(2 mL) and brine (2 mL), dried (MgSO₄) and concentrated to provide thedesired crude carboxylic acid (0.6 g). MS found: (M+Na)⁺=466.

(35g) To a 0° C. mixture of the crude acid from reaction (35f) andtriethylamine (0.46 mL, 2.5 eq.) in tetrahydrofuran (12 mL) was addedisobutyl chloroformate (0.34 mL, 2 eq.). After 30 min at 0° C., sodiumazide (1.76 g, 20 eq.) in water (6 mL) was added. The mixture wasstirred at 0° C. for 30 min before diluted with ethyl acetate (80 mL).The organic layer was washed with water (10 mL), brine (10 mL), dried(MgSO₄), concentrated, and dried under vacuum. The residue was dissolvedin benzene (30 mL) and heated to 70° C. for 1 h. After the reaction wascooled to rt, concentrated ammonia hydroxide (5 mL) was added. Theresulting mixture was stirred at rt for 1 h. Upon removal of solvent,the residue was dissolved in ethyl acetate, washed with water, brine,dried (MgSO₄) and concentrated to provide the crude urea (0.60 g). MSfound: (M+Na)⁺=480.

(35h) A mixture of the crude urea from reaction (35g) and Pd(OH)₂ oncarbon (0.12 g) in methanol (20 mL) was stirred under a balloon ofhydrogen for 2 h. The catalyst was removed by filtration. The filtratewas concentrated to provide the desired phenol (0.41 g). MS found:(M+H)⁺=368.

(35i) A mixture of the crude product (35h),4-(chloromethyl)-2-methylquinoline hydrochloride (0.36 g, 1.58 mmol),Cs₂CO₃ (1.50 g, 4.60 mmol) and sodium iodide (0.24 g, 1.58 mmol) in DMSO(10 mL) was stirred at rt overnight. Purification using reverse phaseHPLC (15-90% acetonitrile/water) provided the desired alkylated product(0.36 g, 52% for 5 steps). MS found: (M+H)⁺=523.

(35j) A mixture of the product from reaction (35i) (0.12 g, 0.19 mmol)and Cs₂CO₃ (0.31 g, 5 eq.) in DMSO (2 mL) was stirred at rt overnight.The reaction mixture was quenched with aqueous ammonium chloride andextracted with ethyl acetate (2×20 mL). The combined extracts werewashed with water, brine, dried (MgSO₄) and concentrated to provide thetitle product (80 mg, 86%). MS found: (M+H)⁺=491.

Example 365-Amino-5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}dihydro-2,4(1H,3H)-pyrimidinedione bis(trifluoroacetate)

To a mixture of the product from reaction (35j) (70 mg, 0.14 mmol) indichloromethane (2 mL) was added trifluoroacetic acid (1 mL). Theresulting solution was stirred at rt for 30 min. Upon removal ofsolvent, the residue was lyophilized to provide the title compound (80mg, 91%). MS found: (M+H)⁺=391.

Example 37(5S)-5-(Dimethylamino)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}dihydro-2,4(1H,3H)-pyrimidinedione bis(trifluoroacetate)

In an analogous procedure to Example 15, the product from Example 31(80.0 mg, 0.132 mmol) was converted to the title compound (12.0 mg,14%). MS found: (M+H)⁺=405.

Tables 1-2 below provide representative Examples, the synthesis of whichis described above, of the compounds of the present invention.

TABLE 1

MS Ex R¹ A W [M + H] 2 Me C(═O) —CH₂— 404 4 Me C(═O) —CH₂CH₂— 418 5—NHBoc C(═O) —CH₂— 505 6 —NH₂ C(═O) —CH₂— 405 7 Me C(═O) —CH₂—CH═CH— 4308 Me C(═O) —CH₂CH₂CH₂— 432 10 Me C(═O) — 390 11 1-piperidinyl C(═O) —459 12 4-morpholinyl C(═O) — 461 13 4-Boc-1- C(═O) — 560 piperazinyl 141-piperazinyl C(═O) — 460 15 4-Me-1-piperazinyl C(═O) — 474 164-(2-phenylethyl)- C(═O) — 564 1-piperazinyl 17 4-neopentyl-1- C(═O) —530 piperazinyl 18 4-isopropyl-1- C(═O) — 502 piperazinyl 19 4-hexyl-1-C(═O) — 544 piperazinyl 20 4-benzyl-1- C(═O) — 550 piperazinyl 21 4-(3-C(═O) — 578 phenylpropyl)- 1-piperazinyl 22 4-(4-nitrophenyl)- C(═O) —581 1-piperazinyl 23 4-(2- C(═O) — 504 hydroxyethyl)-1- piperazinyl 244-butanoic acid-1- C(═O) — 546 piperazinyl 25 4-butanamide-1- C(═O) —559 piperazinyl 26 4-acetyl-1- C(═O) — 502 piperazinyl 27 4-pivaloyl-1-C(═O) — 544 piperazinyl 28 4- C(═O) — 538 (methylsulfonyl)-1-piperazinyl 30 Me CH₂ — 376 31 —NHBoc CH₂ — 477 32 —NH₂ CH₂ — 377 341-piperidinyl CH₂ — 445 35 —NHBoc CH₂ —CH₂— 491 36 —NH₂ CH₂ —CH₂— 391 37—NMe₂ CH₂ — 405

TABLE 2

MS Ex A W Z—U^(a)—X^(a)—Y^(a)—Z^(a) [M + H] 29 CH₂ — 4-(benzyloxy)phenyl[2M − H] 405

The following tables contain additional representative examples of thepresent invention. Each entry in each table is intended to be pairedwith each formula at the start of the table. For example, example 1 inTable 3 is intended to be paired with each of the following formulaeA-DK.

TABLE 3

Ex A R^(A) 3-1  C(═O) (4-quinolinyl)methoxy 3-2  C(═O)(4-quinolinyloxy)methyl 3-3  C(═O) (2-methyl-4-quinolinyloxy)methyl 3-4 C(═O) (2-chloro-4-quinolinyl)methoxy 3-5  C(═O)(2-chloro-4-quinolinyloxy)methyl 3-6  C(═O)(2-isopropyl-4-quinolinyl)methoxy 3-7  C(═O)(2-isopropyl-4-quinolinyloxy)methyl 3-8  C(═O)(2-ethyl-4-quinolinyl)methoxy 3-9  C(═O) (2-ethyl-4-quinolinyloxy)methyl3-10 C(═O) (2-methoxy-4-quinolinyl)methoxy 3-11 C(═O)(2-methoxy-4-quinolinyloxy)methyl 3-12 C(═O)(2-hydroxy-4-quinolinyl)methoxy 3-13 C(═O)(2-hydroxy-4-quinolinyloxy)methyl 3-14 C(═O)(2-trifluoromethyl-4-quinolinyl)methoxy 3-15 C(═O)(2-trifluoromethyl-4-quinolinyloxy)methyl 3-16 C(═O)(2-phenyl-4-quinolinyl)methoxy 3-17 C(═O)(2-phenyl-4-quinolinyloxy)methyl 3-18 C(═O)(2,3-dimethyl-4-quinolinyl)methoxy 3-19 C(═O)(2,3-dimethyl-4-quinolinyloxy)methyl 3-20 C(═O)(2,6-dimethyl-4-quinolinyl)methoxy 3-21 C(═O)(2,6-dimethyl-4-quinolinyloxy)methyl 3-22 C(═O)(2,7-dimethyl-4-quinolinyl)methoxy 3-23 C(═O)(2,7-dimethyl-4-quinolinyloxy)methyl 3-24 C(═O) (5-quinolinyl)methoxy3-25 C(═O) (5-quinolinyloxy)methyl 3-26 C(═O)(7-methyl-5-quinolinyl)methoxy 3-27 C(═O)(7-methyl-5-quinolinyloxy)methyl 3-28 C(═O)(7-methoxy-5-quinolinyl)methoxy 3-29 C(═O)(7-methoxy-5-quinolinyloxy)methyl 3-30 C(═O) (8-quinolinyl)methoxy 3-31C(═O) (8-quinolinyloxy)methyl 3-32 C(═O) 3-(2-methyl-1H-indolyl)methoxy3-33 C(═O) [3-(2-methyl-1H-indolyl)oxy]methyl 3-34 C(═O)3-(1,2-dimethyl-1H-indolyl)methoxy 3-35 C(═O)[3-(1,2-dimethyl-1H-indolyl)oxy]methyl 3-36 C(═O)(2,3-dihydro-4H-1,4-benzothiazin-4-yl)methoxy 3-37 CH₂(4-quinolinyl)methoxy 3-38 CH₂ (4-quinolinyloxy)methyl 3-39 CH₂(2-methyl-4-quinolinyloxy)methyl 3-40 CH₂ (2-chloro-4-quinolinyl)methoxy3-41 CH₂ (2-chloro-4-quinolinyloxy)methyl 3-42 CH₂(2-isopropyl-4-quinolinyl)methoxy 3-43 CH₂(2-isopropyl-4-quinolinyloxy)methyl 3-44 CH₂(2-ethyl-4-quinolinyl)methoxy 3-45 CH₂ (2-ethyl-4-quinolinyloxy)methyl3-46 CH₂ (2-methoxy-4-quinolinyl)methoxy 3-47 CH₂(2-methoxy-4-quinolinyloxy)methyl 3-48 CH₂(2-hydroxy-4-quinolinyl)methoxy 3-49 CH₂(2-hydroxy-4-quinolinyloxy)methyl 3-50 CH₂(2-trifluoromethyl-4-quinolinyl)methoxy 3-51 CH₂(2-trifluoromethyl-4-quinolinyloxy)methyl 3-52 CH₂(2-phenyl-4-quinolinyl)methoxy 3-53 CH₂ (2-phenyl-4-quinolinyloxy)methyl3-54 CH₂ (2,3-dimethyl-4-quinolinyl)methoxy 3-55 CH₂(2,3-dimethyl-4-quinolinyloxy)methyl 3-56 CH₂(2,6-dimethyl-4-quinolinyl)methoxy 3-57 CH₂(2,6-dimethyl-4-quinolinyloxy)methyl 3-58 CH₂(2,7-dimethyl-4-quinolinyl)methoxy 3-59 CH₂(2,7-dimethyl-4-quinolinyloxy)methyl 3-60 CH₂ (5-quinolinyl)methoxy 3-61CH₂ (5-quinolinyloxy)methyl 3-62 CH₂ (7-methyl-5-quinolinyl)methoxy 3-63CH₂ (7-methyl-5-quinolinyloxy)methyl 3-64 CH₂(7-methoxy-5-quinolinyl)methoxy 3-65 CH₂(7-methoxy-5-quinolinyloxy)methyl 3-66 CH₂ (8-quinolinyl)methoxy 3-67CH₂ (8-quinolinyloxy)methyl 3-68 CH₂ 3-(2-methyl-1H-indolyl)methoxy 3-69CH₂ [3-(2-methyl-1H-indolyl)oxy]methyl 3-70 CH₂3-(1,2-dimethyl-1H-indolyl)methoxy 3-71 CH₂[3-(1,2-dimethyl-1H-indolyl)oxy]methyl 3-72 CH₂(2,3-dihydro-4H-1,4-benzothiazin-4-yl)methoxy

Utility

The compounds of formula I are expected to possess matrixmetalloprotease and/or aggrecanase and/or TNF-α inhibitory activity. TheMMP inhibitory activity of the compounds of the present invention isdemonstrated using assays of MMP activity, for example, using the assaydescribed below for assaying inhibitors of MMP activity. The compoundsof the present invention are expected to be bioavailable in vivo asdemonstrated, for example, using the ex vivo assay described below. Thecompounds of formula I are expected to have the ability tosuppress/inhibit cartilage degradation in vivo, for example, asdemonstrated using the animal model of acute cartilage degradationdescribed below.

The compounds provided by this invention should also be useful asstandards and reagents in determining the ability of a potentialpharmaceutical to inhibit MPs. These would be provided in commercialkits comprising a compound of this invention.

Metalloproteinases have also been implicated in the degradation ofbasement membranes to allow infiltration of cancer cells into thecirculation and subsequent penetration into other tissues leading totumor metastasis (Stetler-Stevenson, Cancer and Metastasis Reviews, 9,289-303, 1990). The compounds of the present invention should be usefulfor the prevention and treatment of invasive tumors by inhibition ofthis aspect of metastasis.

The compounds of the present invention should also have utility for theprevention and treatment of osteopenia associated with matrixmetalloprotease-mediated breakdown of cartilage and bone that occurs inosteoporosis patients.

Compounds that inhibit the production or action of TACE and/orAggrecanase and/or MMP's are potentially useful for the treatment orprophylaxis of various inflammatory, infectious, immunological ormalignant diseases or conditions. Thus, the present invention relates toa method of treating various inflammatory, infectious, immunological ormalignant diseases. These include acute infection, acute phase response,age related macular degeneration, alcoholic liver disease, allergy,allergic asthma, anorexia, aneurism, aortic aneurism, asthma,atherosclerosis, atopic dermatitis, autoimmune disease, autoimmunehepatitis, Bechet's disease, cachexia (including cachexia resulting fromcancer or HIV), calcium pyrophosphate dihydrate deposition disease,cardiovascular effects, chronic fatigue syndrome, chronic obstructionpulmonary disease, coagulation, congestive heart failure, cornealulceration, Crohn's disease, enteropathic arthropathy (includinginflammatory bowl disease), Felty's syndrome, fever, fibromyalgiasyndrome, fibrotic disease, gingivitis, glucocorticoid withdrawalsyndrome, gout, graft versus host disease, hemorrhage, HIV infection,hyperoxic alveolar injury, infectious arthritis, inflammation,intermittent hydrarthrosis, Lyme disease, meningitis, multiplesclerosis, myasthenia gravis, mycobacterial infection, neovascularglaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis,polymyositis/dermatomyositis, post-ischaemic reperfusion injury,post-radiation asthenia, psoriasis, psoriatic arthritis, pulmonaryemphysema, pydoderma gangrenosum, relapsing polychondritis, Reiter'ssyndrome, rheumatic fever, rheumatoid arthritis (including juvenilerheumatoid arthritis and adult rheumatoid arthritis), sarcoidosis,scleroderma, sepsis syndrome, Still's disease, shock, Sjogren'ssyndrome, skin inflammatory diseases, solid tumor growth and tumorinvasion by secondary metastases, spondylitis, stroke, systemic lupuserythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener'sgranulomatosis.

Some compounds of the present invention have been shown to inhibit TNFproduction in lipopolysacharride stimulated mice, for example, using theassay for TNF induction in mice and in human whole blood as describedbelow.

Some compounds of the present invention have been shown to inhibitaggrecanase, a key enzyme in cartilage breakdown, as determined by theaggrecanase assay described below.

The compounds of the present invention can be administered alone or incombination with one or more additional anti-inflammatory agents. Theseagents include, but are not limited to, selective COX-2 inhibitors,interleukin-1 antagonists, dihydroorotate synthase inhibitors, p38 MAPkinase inhibitors, TNF-α inhibitors, and TNF-α sequestration agents.

By “administered in combination” or “combination therapy” it is meantthat a compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The term selective COX-2 inhibitors, as used herein, denotes agents thatselectively inhibit COX-2 function. Such agents include, but are notlimited to, celecoxib (Celebrex®), rofecoxib (Vioxx®), meloxicam(Movicox®) etoricoxib, and valdecoxib.

TNF-α sequestration agents that may be used in combination with thecompounds of this invention, are TNF-α binding proteins or anti-TNF-αantibodies. These agents include, but are not limited to, etanercept(Enbrel) infliximab (Remicade®), adalimumab (D2E7), CDP-571 (Humicade®),and CDP-870.

Other anti-inflammatory agents that may be used in combination with thecompounds of this invention, include, but are not limited to,methotrexate, interleukin-1 antagonists (e.g., anakinra (Kineret)),dihydroorotate synthase inhibitors (e.g., leflunomide (Arava)), and p38MAP kinase inhibitors.

Administration of the compounds of the present invention in combinationwith such additional therapeutic agent, may afford an efficacy advantageover the compounds and agents alone, and may do so while permitting theuse of lower doses of each. A lower dosage minimizes the potential ofside effects, thereby providing an increased margin of safety.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g”denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L”denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM”denotes millimolar, “M” denotes molar and “nm” denotes nanometer. “Sigmastands for the Sigma-Aldrich Corp. of St. Louis, Mo.

A compound is considered to be active if it has an IC₅₀ or K_(i) valueof less than about 10 μM for the inhibition of a desired MP. Preferredcompounds of the present invention have K_(i)'s or IC₅₀'s of ≦1 μM. Morepreferred compounds of the present invention have K_(i)'s or IC₅₀'s of≦0.1 μM. Even more preferred compounds of the present invention haveK_(i)'s or IC₅₀'s of ≦0.01 μM. Still more preferred compounds of thepresent invention have K_(i)'s or IC₅₀'s of ≦0.001 μM.

Aggrecanase Enzymatic Assay

A novel enzymatic assay was developed to detect potential inhibitors ofaggrecanase. The assay uses active aggrecanase accumulated in media fromstimulated bovine nasal cartilage (BNC) or related cartilage sources andpurified cartilage aggrecan monomer or a fragment thereof as asubstrate.

The substrate concentration, amount of aggrecanases time of incubationand amount of product loaded for Western analysis were optimized for useof this assay in screening putative aggrecanase inhibitors. Aggrecanaseis generated by stimulation of cartilage slices with interleukin-1(IL-1), tumor necrosis factor alpha (TNF-α) or other stimuli. Matrixmetalloproteinases (MMPs) are secreted from cartilage in an inactive,zymogen form following stimulation, although active enzymes are presentwithin the matrix. We have shown that following depletion of theextracellular aggrecan matrix, active MMPs are released into the culturemedia (Tortorella, M. D. et al. Trans. Ortho. Res. Soc. 1995, 20, 341).Therefore, in order to accumulate BNC aggrecanase in culture media,cartilage is first depleted of endogenous aggrecan by stimulation with500 ng/ml human recombinant IL-β for 6 days with media changes every 2days. Cartilage is then stimulated for an additional 8 days withoutmedia change to allow accumulation of soluble, active aggrecanase in theculture media. In order to decrease the amount of other matrixmetalloproteinases released into the media during aggrecanaseaccumulation, agents which inhibit MMP-1, -2, -3, and -9 biosynthesisare included during stimulation. This BNC conditioned media, containingaggrecanase activity is then used as the source of aggrecanase for theassay. Aggrecanase enzymatic activity is detected by monitoringproduction of aggrecan fragments produced exclusively by cleavage at theGlu373-Ala374 bond within the aggrecan core protein by Western analysisusing the monoclonal antibody, BC-3 (Hughes, C E, et al., Biochem J306:799-804, 1995). This antibody recognizes aggrecan fragments with theN-terminus, 374ARGSVIL, generated upon cleavage by aggrecanase. The BC-3antibody recognizes this neoepitope only when it is at the N-terminusand not when it is present internally within aggrecan fragments orwithin the aggrecan protein core. Other proteases produced by cartilagein response to IL-1 do not cleave aggrecan at the Glu373-Ala374aggrecanase site; therefore, only products produced upon cleavage byaggrecanase are detected. Kinetic studies using this assay yield a Km of1.5+/−0.35 uM for aggrecanase.

To evaluate inhibition of aggrecanase, compounds are prepared as 10 mMstocks in DMSO, water or other solvents and diluted to appropriateconcentrations in water. Drug (50 ul) is added to 50 ul ofaggrecanase-containing media and 50 ul of 2 mg/ml aggrecan substrate andbrought to a final volume of 200 ul in 0.2 M Tris, pH 7.6, containing0.4 M NaCl and 40 mM CaCl₂. The assay is run for 4 hr at 37° C.,quenched with 20 mM EDTA and analyzed for aggrecanase-generatedproducts. A sample containing enzyme and substrate without drug isincluded as a positive control and enzyme incubated in the absence ofsubstrate serves as a measure of background.

Removal of the glycosaminoglycan side chains from aggrecan is necessaryfor the BC-3 antibody to recognize the ARGSVIL epitope on the coreprotein. Therefore, for analysis of aggrecan fragments generated bycleavage at the Glu373-Ala374 site, proteoglycans and proteoglycanfragments are enzymatically deglycosylated with chondroitinase ABC (0.1units/10 ug GAG) for 2 hr at 37° C. and then with keratanase (0.1units/10 ug GAG) and keratanase II (0.002 units/10 ug GAG) for 2 hr at37° C. in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCl, pH6.5. After digestion, aggrecan in the samples is precipitated with 5volumes of acetone and resuspended in 30 ul of Tris glycine SDS samplebuffer (Novex) containing 2.5% beta mercaptoethanol. Samples are loadedand then separated by SDS-PAGE under reducing conditions with 4-12%gradient gels, transferred to nitrocellulose and immunolocated with1:500 dilution of antibody BC3. Subsequently, membranes are incubatedwith a 1:5000 dilution of goat anti-mouse IgG alkaline phosphatasesecond antibody and aggrecan catabolites visualized by incubation withappropriate substrate for 10-30 minutes to achieve optimal colordevelopment. Blots are quantitated by scanning densitometry andinhibition of aggrecanase determined by comparing the amount of productproduced in the presence versus absence of compound.

TNF PBMC Assay

Human peripheral blood mononuclear cells (PBMC) were obtained fromnormal donor blood by leukophoresis and isolated by Ficoll-Paque densityseparation. PBMCs were suspended in 0.5 ml RPMI 1640 with no serum at2×10⁶ cells/ml in 96 well polystyrene plates. Cells were preincubated 10minutes with compound, then stimulated with 1 μg/ml LPS(Lipopolysaccharide, Salmonella typhimurium) to induce TNF production.After an incubation of 5 hours at 37° C. in 95% air, 5% CO₂ environment,culture supernatants were removed and tested by standard sandwich ELISAfor TNF production.

TNF Human whole Blood Assay

Blood is drawn from normal donors into tubes containing 143 USP units ofheparin/10 ml. 225 ul of blood is plated directly into sterilepolypropylene tubes. Compounds are diluted in DMSO/serum free media andadded to the blood samples so the final concentration of compounds are50, 10, 5, 1, 0.5, 0.1, and 0.01 μM. The final concentration of DMSOdoes not exceed 0.5%. Compounds are preincubated for 15 minutes beforethe addition of 100 ng/ml LPS. Plates are incubated for 5 hours in anatmosphere of 5% CO₂ in air. At the end of 5 hours, 750 ul of serum freemedia is added to each tube and the samples are spun at 1200 RPM for 10minutes. The supernatant is collected off the top and assayed forTNF-alpha production by a standard sandwich ELISA. The ability ofcompounds to inhibit TNF-alpha production by 50% compared to DMSOtreated cultures is given by the IC₅₀ value.

TNF Induction in Mice

Test compounds are administered to mice either I.P. or P.O. at timezero. Immediately following compound administration, mice receive anI.P. injection of 20 mg of D-galactosamine plus 10 μg oflipopolysaccharide. One hour later, animals are anesthetized and bled bycardiac puncture. Blood plasma is evaluated for TNF levels by an ELISAspecific for mouse TNF. Administration of representative compounds ofthe present invention to mice results in a dose-dependent suppression ofplasma TNF levels at one hour in the above assay.

MMP Assays

The enzymatic activities of recombinant MMP-1, 2, 3, 7, 8, 9, 10, 12,13, 14, 15, and 16 were measured at 25° C. with a fluorometric assay(Copeland, R. A. et al. Bioorganic Med. Chem. Lett. 1995, 5, 1947-1952).Final enzyme concentrations in the assay were between 0.05 and 10 nMdepending on the enzyme and the potency of the inhibitor tested. Thepermisive peptide substrate, MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH₂, waspresent at a final concentration of 10 uM in all assays. Initialvelocities, in the presence or absence of inhibitor, were measured asslopes of the linear portion of the product progress curves. IC50 valueswere determined by plotting the inhibitor concentration dependence ofthe fractional velocity for each enzyme, and fitting the data bynon-linear least squares methods to the standard isotherm equation(Copeland, R. A. Enzymes: A practical Introduction to Structure,Mechanism and Data Analysis, Wiley-VHC, New York, 1996, pp 187-223). Allof the compounds studied here were assumed to act as competitiveinhibitors of the enzyme, binding to the active site Zn atom aspreviously demonstrated by crystallographic studies of MMP-3 complexedwith related hydroxamic acids (Rockwell, A. et al. J. Am. Chem. Soc.1996, 118, 10337-10338). Based on the assumption of competitiveinhibiton, the IC50 values were converted to Ki values as previouslydescribed.

Compounds tested in the above assay are considered to be active if theyexhibit a K_(i) of ≦10 μM. Preferred compounds of the present inventionhave K_(i)'s of ≦1 μM. More preferred compounds of the present inventionhave K_(i)'s of ≦0.1 μM. Even more preferred compounds of the presentinvention have K_(i)'s of ≦0.01 μM. Still more preferred compounds ofthe present invention have K_(i)'s of ≦0.001 μM.

Using the methodology described above, a number of compounds of thepresent invention were found to exhibit K_(i)'s of ≦10 μM, therebyconfirming the utility of the compounds of the present invention.

Dosage and Formulation

The compounds of the present invention can be administered orally usingany pharmaceutically acceptable dosage form known in the art for suchadministration. The active ingredient can be supplied in solid dosageforms such as dry powders, granules, tablets or capsules, or in liquiddosage forms, such as syrups or aqueous suspensions. The activeingredient can be administered alone, but is generally administered witha pharmaceutical carrier. A valuable treatise with respect topharmaceutical dosage forms is Remington's Pharmaceutical Sciences, MackPublishing.

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.An effective but non-toxic amount of the compound desired can beemployed as an antiinflammatory and antiarthritic agent.

The compounds of this invention can be administered by any means thatproduces contact of the active agent with the agent's site of action inthe body of a mammal. They can be administered by any conventional meansavailable for use in conjunction with pharmaceuticals, either asindividual therapeutic agents or in a combination of therapeutic agents.They can be administered alone, but generally administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 mg/kg/day. For a normal male adult human of approximately 70kg of body weight, this translates into a dosage of 70 to 1400 mg/day.Intravenously, the most preferred doses will range from about 1 to about10 mg/kg/minute during a constant rate infusion. Advantageously,compounds of the present invention may be administered in a single dailydose, or the total daily dosage may be administered in divided doses oftwo, three, or four times daily.

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wallknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittant throughout the dosageregimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients, orcarriers (collectively referred to herein as carrier materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamallar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance. In general, water, a suitableoil, saline, aqueous dextrose (glucose), and related sugar solutions andglycols such as propylene glycol or polyethylene glycols are suitablecarriers for parenteral solutions. Solutions for parenteraladministration preferably contain a water soluble salt of the activeingredient, suitable stabilizing agents, and if necessary, buffersubstances. Antioxidizing agents such as sodium bisulfite, sodiumsulfite, or ascorbic acid, either alone or combined, are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

The compounds of the present invention may be administered incombination with a second therapeutic agent, especially non-steroidalanti-inflammatory drugs (NSAID's). The compound of Formula I and suchsecond therapeutic agent can be administered separately or as a physicalcombination in a single dosage unit, in any dosage form and by variousroutes of administration, as described above.

The compound of Formula I may be formulated together with the secondtherapeutic agent in a single dosage unit (that is, combined together inone capsule, tablet, powder, or liquid, etc.). When the compound ofFormula I and the second therapeutic agent are not formulated togetherin a single dosage unit, the compound of Formula I and the secondtherapeutic agent may be administered essentially at the same time, orin any order; for example the compound of Formula I may be administeredfirst, followed by administration of the second agent. When notadministered at the same time, preferably the administration of thecompound of Formula I and the second therapeutic agent occurs less thanabout one hour apart, more preferably less than about 5 to 30 minutesapart.

Preferably the route of administration of the compound of Formula I isoral. Although it is preferable that the compound of Formula I and thesecond therapeutic agent are both administered by the same route (thatis, for example, both orally), if desired, they may each be administeredby different routes and in different dosage forms (that is, for example,one component of the combination product may be administered orally, andanother component may be administered intravenously).

The dosage of the compound of Formula I when administered alone or incombination with a second therapeutic agent may vary depending uponvarious factors such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration, the age,health and weight of the recipient, the nature and extent of thesymptoms, the kind of concurrent treatment, the frequency of treatment,and the effect desired, as described above. Particularly when providedas a single dosage unit, the potential exists for a chemical interactionbetween the combined active ingredients. For this reason, when thecompound of Formula I and a second therapeutic agent are combined in asingle dosage unit they are formulated such that although the activeingredients are combined in a single dosage unit, the physical contactbetween the active ingredients is minimized (that is, reduced). Forexample, one active ingredient may be enteric coated. By enteric coatingone of the active ingredients, it is possible not only to minimize thecontact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. One of theactive ingredients may also be coated with a sustained-release materialwhich effects a sustained-release throughout the gastrointestinal tractand also serves to minimize physical contact between the combined activeingredients. Furthermore, the sustained-released component can beadditionally enteric coated such that the release of this componentoccurs only in the intestine. Still another approach would involve theformulation of a combination product in which the one component iscoated with a sustained and/or enteric release polymer, and the othercomponent is also coated with a polymer such as a lowviscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of osteoarthritis or rheumatoidarthritis, which comprise one or more containers containing apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I. Such kits may further include, if desired,one or more of various conventional pharmaceutical kit components, suchas, for example, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, mayalso be included in the kit.

In the present disclosure it should be understood that the specifiedmaterials and conditions are important in practicing the invention butthat unspecified materials and conditions are not excluded so long asthey do not prevent the benefits of the invention from being realized.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes, and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein; A is C(═O), C(═S) or CH₂; B is O or S; L is O or S; W is selected from (CR^(a)R^(a1))_(m), C₂₋₃ alkenylene, and C₂₋₃ alkynylene; Z is selected from: a C₆₋₁₀ aryl substituted with 0-5 R^(b) and a 5-14 membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-5 R^(b); U^(a) is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH), C(O)O, OC(O), C(O)NR^(a1), NR^(a1)C(O), OC(O)O, OC(O)NR^(a1), NR^(a1)C(O)O, NR^(a1)C(O)NR^(a1), S(O)_(p), S(O)_(p)NR^(a1), NR^(a1)S(O)_(p), and NR^(a1)SO₂NR^(a1); X^(a) is absent or is selected from C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene; Y^(a) is absent or is selected from O, NR^(a1), S(O)_(p), and C(O); provided that U^(a)—X^(a)—Y^(a) forms a linker group of two or more backbone atoms; Z^(a) is a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-5 R^(c); provided that Z^(a) is other than dihydro-2-oxo-thien-3-yl; provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p), or S(O)_(p)—S(O)_(p) group; R¹ is selected from CHF₂, CH₂F, CF₃, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆ alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1), (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)OC(O)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)OC(O)OR^(a1), (CR^(a)R^(a1))_(r1)OC(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r1)NR^(a)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)NR^(a)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)NR^(a)SO₂NR^(a)R^(a1), a C₃₋₁₃ carbocycle substituted with 0-5 R^(d), and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-5 R^(d); Q, at each occurrence, is independently selected from H, CHF₂, CH₂F, CF₃, a C₃₋₁₃ carbocycle substituted with 0-5 R^(d), and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-5 R^(d); R^(a), at each occurrence, is independently selected from H, C₁₋₆ alkyl, phenyl, and benzyl; R^(a1), at each occurrence, is independently selected from H, C₁₋₆ alkyl substituted with 0-1 R^(e), C₂₋₆ alkenyl substituted with 0-1 R^(e), C₂₋₆ alkynyl substituted with 0-1 R^(e), and —(CH₂)_(r)-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p), and substituted with 0-3 R^(e); alternatively, R^(a) and R^(a1), when attached to a nitrogen, are taken together with the nitrogen to which they are attached, form a 5 or 6 membered heterocycle comprising carbon atoms and 0-1 additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p); R^(a2), at each occurrence, is independently selected from C₁₋₄ alkyl, phenyl, and benzyl; R^(a3), at each occurrence, is independently selected from H, C₁₋₆ alkyl substituted with 0-1 R^(c1), C₂₋₆ alkenyl substituted with 0-1 R^(c1), C₂₋₆ alkynyl substituted with 0-1 R^(c1), and —(CH₂)_(r)-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p), and substituted with 0-3 R^(c1); R^(b), at each occurrence, is independently selected from C₁₋₆ alkyl substituted with 0-1 R^(c1), OR^(a), SR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), C(S)NR^(a)R^(a1), NR^(a)C(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), NR^(a)C(O)OR^(a), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, CF₂CF₃, CHF₂, CH₂F, and phenyl; R^(c), at each occurrence, is independently selected from H, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, CF₃, CF₂CF₃, CH₂F, CHF₂, (CR^(a)R^(a1))_(r)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(═NCN)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(═NR^(a))NR^(a)R^(a1), (CR^(a)R^(a1))_(r)C(═NOR^(a))NR^(a)R^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)OH, (CR^(a)R^(a1))_(r1)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(S)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(S)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)OC(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1), (CR^(a)R^(a1))_(r)NR^(a)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1), (CR^(a)R_(a1))_(r)NR^(a)SO₂R^(a3), (CR^(a)R^(a1))_(r)NR^(a)SO₂NR^(a)R^(a1); C₁₋₆ alkyl substituted with 0-2 R^(c1); C₂₋₆ alkenyl substituted with 0-2 R^(c1); C₂₋₆ alkynyl substituted with 0-2 R^(c1); (CR^(a)R^(a1))_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(c1); and (CR^(a)R^(a1))_(r)-5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-2 R^(c1); alternatively, when two R^(c) groups are attached to the same carbon atom, they form a spiro ring C that is a 3-11 membered carbocycle or heterocycle substituted with 0-2 R^(c1) and comprising: carbon atoms, 0-4 ring heteroatoms selected from O, N, and S(O)_(p), and 0-2 double bonds, provided that ring C contains other than a S—S, O—O, or S—O bond; alternatively, when two R^(c) groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-7 membered carbocyclic or heterocyclic ring D substituted with 0-2 R^(c1) and consisting of carbon atoms, 0-2 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and 0-3 double bonds; R^(c1), at each occurrence, is independently selected from H, C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, and CHF₂; R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl substituted with 0-2 R^(e), C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a), C(O)NR^(a)R^(a1), C(S)NR^(a)R^(a1), R^(a)NC(O)NR^(a)R^(a1), OC(O)NR^(a)R^(a1), R^(a)NC(O)OR^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), NR^(a)S(O)₂NR^(a)R^(a1), OS(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, CF₂CF₃, (CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-2 R^(e), and a (CH₂)_(r)-5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-2 R^(e); R^(e), at each occurrence, is independently selected from H, C₁₋₆ alkyl, OR^(a), Cl, F, Br, I, ═O, —CN, NO₂, NR^(a)R^(a), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a), R^(a)NC(O)NR^(a)R^(a), OC(O)NR^(a)R^(a), R^(a)NC(O)OR^(a), S(O)₂NR^(a)R^(a), NR^(a)S(O)₂R^(a2), NR^(a)S(O)₂NR^(a)R^(a), OS(O)₂NR^(a)R^(a), NR^(a)S(O)₂R^(a2), S(O)_(p)R^(a2), CF₃, OCF₃, CF₂CF₃, CH₂F, and CHF₂; m, at each occurrence, is selected from 0, 1, 2 and 3; p, at each occurrence, is selected from 0, 1, and 2; r, at each occurrence, is selected from 0, 1, 2, 3, and 4; r1, at each occurrence, is selected from 0, 1, 2, 3, and
 4. 2. A compound according to claim 1, wherein; W is (CHR^(a))_(m) or C₂₋₃ alkenylene; U^(a) is absent or is selected from: O, NR^(a1), C(O), CR^(a)(OH), C(O)O, C(O)NR^(a1), NR^(a1)C(O), S(O)_(p), S(O)_(p)NR^(a1), and NR^(a1)S(O)_(p); X^(a) is absent or is selected from C₁₋₄ alkylene, C₂₋₄ alkenylene, and C₂₋₄ alkynylene; Y^(a) is absent or is selected from O and NR^(a1); provided that U^(a)—X^(a)—Y^(a) forms a linker group of two or more backbone atoms; R¹ is selected from CHF₂, CH₂F, CF₃, C₁₋₆ alkylene-Q, C₂₋₆ alkenylene-Q, C₂₋₆ alkynylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1), (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r1)NR^(a)SO₂(CR^(a)R^(a1))_(r)-Q, a C₃₋₁₀ carbocycle substituted with 0-5 R^(d), and a 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-5 R^(d); Q, at each occurrence, is independently selected from H, CF₃, a C₃₋₁₃ carbocycle substituted with 0-5 R^(d), and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-5 R^(d); R^(c), at each occurrence, is independently selected from H, OR^(a), Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1), (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₁₋₆ alkyl substituted with 0-1 R^(c1); C₂₋₆ alkenyl substituted with 0-1 R^(c1); C₂₋₆ alkynyl substituted with 0-1 R^(c1); (CH₂)_(r)—C₃₋₆ carbocycle substituted with 0-2 R^(c1); and (CH₂)_(r)-5-6 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-2 R^(c1); alternatively, when two R^(c) groups are attached to the same carbon atom, they form a spiro ring C that is a 3-8 membered carbocycle or heterocycle substituted with 0-2 R^(c1) and comprising: carbon atoms, 0-4 ring heteroatoms selected from O, N, and S(O)_(p), and 0-2 double bonds, provided that ring C contains other than a S—S, O—O, or S—O bond; and alternatively, when two R^(c) groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-7 membered carbocyclic or heterocyclic ring D substituted with 0-2 R^(c1) and consisting of carbon atoms, 0-2 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and 0-3 double bonds.
 3. A compound according to claim 2, wherein; A is C(═O) or CH₂; B is O; L is O; Z is selected from: phenyl substituted with 0-5 R^(b); naphthyl substituted with 0-5 R^(b); and a 5-14 membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-5 R^(b); U^(a) is absent or is selected from: O, NR^(a1), C(O), C(O)NR^(a1), NR^(a1)C(O), and S(O)_(p); provided that U^(a)—X^(a)—Y^(a) forms a linker group of two or more backbone atoms; Z^(a) is a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-5 R^(c); provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; Q, at each occurrence, is independently selected from H, a C₃₋₁₀ carbocycle substituted with 0-3 R^(d), and a 5-14 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-3 R^(d); R^(a), at each occurrence, is independently selected from H and C₁₋₆ alkyl; R^(a1), at each occurrence, is independently selected from H, C₁₋₆ alkyl, phenyl, and benzyl; alternatively, R^(a) and R^(a1), when attached to a nitrogen, are taken together with the nitrogen to which they are attached, form a 5 or 6 membered heterocycle comprising carbon atoms and 0-1 additional heteroatoms selected from N, NR^(a2), O, and S(O)_(p); R^(a3), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, and —(CH₂)_(r)-3-8 membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-2 ring heteroatoms selected from N, NR^(a2), O, and S(O)_(p), and substituted with 0-3 R^(c1); R^(c), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1), (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₃₋₆ carbocycle substituted with 0-2 R^(c1); and 5-6 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-2 R^(c1); alternatively, when two R^(c) groups are attached to the same carbon atom, they form a spiro ring C that is a 3-8 membered carbocycle or heterocycle substituted with 0-2 R^(c1) and comprising: carbon atoms, 0-4 ring heteroatoms selected from O, N, and S(O)_(p), and 0-2 double bonds, provided that ring C contains other than a S—S, O—O, or S—O bond; alternatively, when two R^(c) groups are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-6 membered carbocyclic or heterocyclic ring D substituted with 0-2 R^(c1) and consisting of carbon atoms, 0-2 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and 0-3 double bonds; R^(c1), at each occurrence, is independently selected from H, C₁₋₄ alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)OR^(a), and C(O)NR^(a)R^(a1); R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl substituted with 0-2 R^(e), OR^(a), Cl, F, Br, ═O, —CN, NO₂, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a), C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, (CH₂)_(r)—C₃₋₆ carbocycle substituted with 0-2 R^(e), and a 5-6 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p); and R^(e), at each occurrence, is independently selected from H, C₁₋₄ alkyl, OR^(a), Cl, F, Br, I, ═O, CF₃, —CN, NO₂, C(O)OR^(a), and C(O)NR^(a)R^(a).
 4. A compound according to claim 3, wherein; W is (CH₂)_(m) or C₂₋₃ alkenylene; Z selected from: phenyl substituted with 0-3 R^(b); naphthyl substituted with 0-3 R^(b); a 5-10 membered heteroaryl substituted with 0-3 R^(b) and selected from the group: furanyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, thiophenyl, triazinyl, pyridyl, pyrimidinyl, pyridoimidazole, indolyl, benzimidazolyl, benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, indazolyl, isobenzofuranyl, isoindazolyl, isoindolyl, isoquinolinyl, and quinazolinyl; Z^(a) is a 5-10 membered heterocycle substituted with 0-3 R^(c) and selected from the group: furanyl, tetrahydrofuranyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl, isoxazolyl, 4,5-dihydro-isoxazolyl, thiophenyl, triazinyl, pyridyl, pyrimidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridoimidazole, pyrrolidinyl, pyrrolinyl, indolyl, indolinyl, benzimidazolyl, benzothiazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydro-isoquinolinyl, indazolyl, isobenzofuranyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, methylenedioxyphenyl, quinazolinyl, thiadiazinyl, and 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl; provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; Q, at each occurrence, is independently selected from H, a C₃₋₆ carbocycle substituted with 0-3 R^(d), and a 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-3 R^(d); R^(a), at each occurrence, is independently selected from H and C₁₋₆ alkyl; R^(a1), at each occurrence, is independently selected from H, C₁₋₆ alkyl, phenyl, and benzyl; R^(a3), at each occurrence, is independently selected from H, C₁₋₆ alkyl, phenyl, and benzyl; R^(b), at each occurrence, is independently selected from C₁₋₄ alkyl, OR^(a), Cl, F, ═O, NR^(a)R^(a1), C(O)R^(a), C(O)OR^(a), C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), S(O)_(p)R^(a3), and CF₃; R^(c), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)C(O)R^(a1), (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1), (CR^(a)R^(a1))_(r)NR^(a)SO₂R^(a3); C₃₋₆ carbocycle substituted with 0-2 R^(c1); and 5-6 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-2 R^(c1); and R^(d), at each occurrence, is independently selected from C₁₋₆ alkyl substituted with 0-1 R^(e), OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), C(O)R^(a1), C(O)OR^(a), C(O)NR^(a)R^(a1), S(O)₂NR^(a)R^(a1), NR^(a)S(O)₂R^(a3), S(O)_(p)R^(a3), CF₃, and (CH₂)_(r)-phenyl substituted with 0-2 R^(e).
 5. A compound according to claim 4, wherein; Z is selected from: phenyl substituted with 0-3 R^(b); naphthyl substituted with 0-3 R^(b); thiophenyl substituted with 0-2 R^(b); oxazolyl substituted with 0-1 R^(b); isoxazolyl substituted with 0-1 R^(b); and thiazolyl substituted with 0-1 R^(b); U^(a) is absent or is O; X^(a) is selected from CH₂ and CH₂CH₂; Y^(a) is absent or is O; provided that U^(a)—X^(a)—Y^(a) forms a linker group of two or more backbone atoms; Z^(a) is selected from pyridyl substituted with 0-3 R^(c); indolyl substituted with 0-3 R^(c); quinolinyl substituted with 0-3 R^(c); benzimidazolyl substituted with 0-3 R^(c); and 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl substituted with 0-3 R^(c); provided that Z, U^(a), Y^(a), and Z^(a) do not combine to form a N—N, N—O, O—N, O—O, S(O)_(p)—O, O—S(O)_(p) or S(O)_(p)—S(O)_(p) group; R¹ is selected from C₁₋₆ alkylene-Q, (CR^(a)R^(a1))_(r1)OR^(a1), (CR^(a)R^(a1))_(r1)NR^(a)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)NR^(a)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r1)NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r)NR^(a)C(O)OR^(a1), (CR^(a)R^(a1))_(r1)S(O)_(p)(CR^(a)R^(a1))_(r)-Q, (CR^(a)R^(a1))_(r1)SO₂NR^(a)R^(a1), a C₃₋₆ carbocycle substituted with 0-3 R^(d), and a 5-10 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)_(p), and substituted with 0-3 R^(d); and R^(c), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), (CR^(a)R^(a1))_(r)SO₂NR^(a)R^(a1), and phenyl.
 6. A compound according to claim 5, wherein; R¹ is selected from C₁₋₆ alkylene-Q, NR^(a)(CR^(a)R^(a1))_(r)-Q, C(O)(CR^(a)R^(a1))_(r)-Q, C(O)OR^(a1), C(O)NR^(a)R^(a1), NR^(a)C(O)(CR^(a)R^(a1))_(r)-Q, NR^(a)C(O)OR^(a1), S(O)_(p)(CR^(a)R^(a1))_(r)-Q, SO₂NR^(a)R^(a1), cyclopropyl substituted with 0-1 R^(d), cyclopentyl substituted with 0-1 R^(d), cyclohexyl substituted with 0-1 R^(d), phenyl substituted with 0-2 R^(d), and a heterocycle substituted with 0-3 R^(d), wherein the heterocycle is selected from pyridyl, quinolinyl, thiazolyl, furanyl, morpholinyl, imidazolyl, isoxazolyl, piperidinyl, and piperazinyl; Q, at each occurrence, is independently selected from H, cyclopropyl substituted with 0-1 R^(d), cyclopentyl substituted with 0-1 R^(d), cyclohexyl substituted with 0-1 R^(d), phenyl substituted with 0-2 R^(d), and a heteroaryl substituted with 0-3 R^(d), wherein the heteroaryl is selected from pyridyl, quinolinyl, thiazolyl, furanyl, imidazolyl, and isoxazolyl; R^(c), at each occurrence, is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, OR^(a), Cl, F, Br, ═O, NR^(a)R^(a1), CF₃, (CR^(a)R^(a1))_(r)C(O)R^(a1), (CR^(a)R^(a1))_(r)C(O)OR^(a1), (CR^(a)R^(a1))_(r)C(O)NR^(a)R^(a1), (CR^(a)R^(a1))_(r)S(O)_(p)R^(a3), and phenyl; and r, at each occurrence, is selected from 0, 1, 2, and
 3. 7. A compound according to claim 1, wherein the compound is selected from the group: 5-methyl-5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-methyl-5-(2-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}ethyl)-2,4,6(1H,3H,5H)-pyrimidinetrione; tert-butyl 5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4,6-trioxohexahydro-5-pyrimidinylcarbamate; 5-amino-5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-methyl-5-((2E)-3-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-propenyl)-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-methyl-5-(3-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}propyl)-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-methyl-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-(1-piperidinyl)-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-(4-morpholinyl)-2,4,6(1H,3H,5H)-pyrimidinetrione; tert-butyl 4-(5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6-trioxohexahydro-5-pyrimidinyl)-1-piperazinecarboxylate; 5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-(1-piperazinyl)-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-(4-methyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(2-phenylethyl)-1-piperazinyl]-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-(4-neopentyl-1-piperazinyl)-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-(4-isopropyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-(4-hexyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-(4-benzyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(3-phenylpropyl)-1-piperazinyl]-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(4-nitrophenyl)-1-piperazinyl]-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-[4-(2-hydroxyethyl)-1-piperazinyl]-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H,5H)-pyrimidinetrione; 4-[4-(5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6-trioxohexahydro-5-pyrimidinyl)-1-piperazinyl]butanoic acid; N-methyl-4-[4-(5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6-trioxohexahydro-5-pyrimidinyl)-1-piperazinyl]butanamide; 5-(4-acetyl-1-piperazinyl)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-[4-(2,2-dimethylpropanoyl)-1-piperazinyl]-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-[4-(methylsulfonyl)-1-piperazinyl]-2,4,6(1H,3H,5H)-pyrimidinetrione; 5-methyl-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}dihydro-2,4(1H,3H)-pyrimidinedione; tert-butyl (5S)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2,4-dioxohexahydro-5-pyrimidinylcarbamate; (5S)-5-amino-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}dihydro-2,4(1H,3H)-pyrimidinedione; 5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-5-(4-piperidinyl)dihydro-2,4(1H,3H)-pyrimidinedione; tert-butyl 5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}-2,4-dioxohexahydro-5-pyrimidinylcarbamate; 5-amino-5-{4-[(2-methyl-4-quinolinyl)methoxy]benzyl}dihydro-2,4(1H,3H)-pyrimidinedione; (5S)-5-(dimethylamino)-5-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}dihydro-2,4(1H,3H)-pyrimidinedione; or a pharmaceutically acceptable salt form thereof.
 8. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt form thereof.
 9. A method of treating a disease or condition selected from Crohn's disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound according to claim
 1. 10. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt form thereof.
 11. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt form thereof.
 12. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt form thereof.
 13. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 5 or a pharmaceutically acceptable salt form thereof.
 14. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 6 or a pharmaceutically acceptable salt form thereof.
 15. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt form thereof.
 16. A method of treating a disease or condition selected from Crohn's disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound according to claim
 2. 17. A method of treating a disease or condition selected from Crohn's disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound according to claim
 3. 18. A method of treating a disease or condition selected from Crohn's disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound according to claim
 4. 19. A method of treating a disease or condition selected from Crohn's disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound according to claim
 5. 20. A method of treating a disease or condition selected from Crohn's disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound according to claim
 6. 21. A method of treating a disease or condition selected from Crohn's disease, psoriasis, psoriatic arthritis, and rheumatoid arthritis, comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound according to claim
 7. 